Indole derivatives useful for the treatment of diseases

ABSTRACT

The invention relates to indole derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The indole derivatives according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

[0001] This invention relates to β2 agonists of the indole derivativesfamily of general formula:

[0002] in which R₁, R₁′, R₂, R₃, Q and A have the meanings indicatedbelow,

[0003] and to processes for the preparation of, intermediates used inthe preparation of, compositions containing and the uses of, suchderivatives.

[0004] Adrenoceptors are members of the large G-protein coupled receptorsuper-family. The adrenoceptor subfamily is itself divided into the αand β subfamilies with the β sub-family being composed of at least 3receptor sub-types: β1, β2 and β3. These receptors exhibit differentialexpression patterns in tissues of various systems and organs of mammals.β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells(e.g. vascular, bronchial, uterine or intestinal smooth muscles),whereas β3 adrenergic receptors are mainly expressed in fat tissues(therefore β3 agonists could potentially be useful in the treatment ofobesity and diabetes) and β1 adrenergic receptors are mainly expressedin cardiac tissues (therefore β1 agonists are mainly used as cardiacstimulants).

[0005] The pathophysiology and treatments of airway diseases have beenextensively reviewed in the literature (for reference see Barnes, P. J.Chest, 1997, 111:2, pp 17S-26S and Bryan, S. A. et al, Expert Opinion oninvestigational drugs, 2000, 9:1, pp25-42) and therefore only a briefsummary will be included here to provide some background information.

[0006] Glucocorticosteroids, anti-leukotrienes, theophylline, cromones,anti-cholinergics and β2 agonists constitute drug classes that arecurrently used to treat allergic and non-allergic airways diseases suchas asthma and chronic obstructive airways disease (COPD). Treatmentguidelines for these diseases include both short and long acting inhaledβ2 agonists. Short acting, rapid onset β2 agonists are used for “rescue”bronchodilation, whereas, long-acting forms provide sustained relief andare used as maintenance therapy.

[0007] Bronchodilation is mediated via agonism of the β2 adrenoreceptorexpressed on airway smooth muscle cells, which results in relaxation andhence bronchodilation. Thus, as functional antagonists, β2 agonists canprevent and reverse the effects of all bronchoconstrictor substances,including leukotriene D4 (LTD4), acetylcholine, bradykinin,prostaglandins, histamine and endothelins. Because β2 receptors are sowidely distributed in the airway, β2 agonists may also affect othertypes of cells that play a role in asthma. For example, it has beenreported that β2 agonists may stabilize mast cells. The inhibition ofthe release of bronchoconstrictor substances may be how β2 agonistsblock the bronchoconstriction induced by allergens, exercise and coldair. Furthermore, β2 agonists inhibit cholinergic neurotransmission inthe human airway, which can result in reduced cholinergic-reflexbronchoconstriction.

[0008] In addition to the airways, it has also been established that β2adrenoceptors are also expressed in other organs and tissues and thus β2agonists, such as those described in the present invention, may haveapplication in the treatment of other diseases such as, but not limitedto those of the nervous system, premature labor, congestive heartfailure, depression, inflammatory and allergic skin diseases, psoriasis,proliferative skin diseases, glaucoma and in conditions where there isan advantage in lowering gastric acidity, particularly in gastric andpeptic ulceration.

[0009] However, numerous β2 agonists are limited in their use due totheir low selectivity or adverse side-effects driven by high systemicexposure and mainly mediated through action at β2 adrenoreceptorsexpressed outside the airways (muscle tremor, tachycardia, palpitations,restlessness). Therefore there is a need for improved agents in thisclass.

[0010] Accordingly, there is still a need for novel β2 agonists thatwould have an appropriate pharmacological profile, for example in termsof potency. In this context, the present invention relates to novel β2agonists of the indole derivatives family.

[0011] Various indole derivatives have already been synthesised. Forexample, patent application EP 801 060 discloses dihydroindolederivatives having a selective β3 agonist activity, of formula:

[0012] wherein R₁ may be an optionally substituted phenyl (1 to 3substitutents which may be selected from hydroxyl and hydroxyalkyl), R₂may be hydrogen, R₃ is hydrogen or alkyl, Z is —CH₂— or —CH₂—CH₂—, Y maybe —NR₇— (R₇ may be hydrogen or alkyl) and R₄ and R₅ are independentlyhydrogen, COOR₆, COONR₆R₆, CHO, COR₆, CH₂OH, CH₂OCH₂COOR₆ andCH₂OCH₂CH₂OR₆ (R₆ is hydrogen or alkyl).

[0013] Patent application EP 822 185 also discloses selective β3agonists of formula:

[0014] wherein R₁ may be an optionally substituted phenyl with 1 to 3substitutents selected from hydroxy and hydroxyalkyl, R₂ may behydrogen, and R₃ may be hydrogen or alkyl optionally independentlysubstituted with one or more halo atoms.

[0015] However, none of the indole derivatives synthetised so far haveshown β2 agonist activity with high potency (they are all selective β3agonists) allowing them to be used as efficient drugs in the treatmentof the β2-mediated diseases and/or conditions, in particular allergicand non-allergic airways diseases or other diseases such as thosepreviously cited.

[0016] It has now been found that the new indole derivatives of formula(1) below are agonists of the β2 receptors, that are particularly usefulfor the treatment of β2-mediated diseases and/or conditions, by showinggood potency, in particular when administered via the inhalation route.

[0017] The invention relates to indole derivatives of general formula(1) below:

[0018] a) wherein

[0019] Q is a saturated 1 to 4 carbon atom chain substituted with a(C₁-C₄)alkyl;

[0020] R₁ and R₁′ are the same or different and are selected fromhydrogen and (C₁-C₄)alkyl provided that when R₁ and R₁′ are both C₁-C₄alkyl, they are identical;

[0021] R₂ is selected from hydrogen, (C₁-C₄)alkyl and benzyl optionallysubstituted with 1, 2 or 3 groups selected from hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl and NR₉R₁₀ wherein R₉ andR₁₀ are identical or different and are selected from hydrogen and(C₁-C₄)alkyl;

[0022] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl optionally substituted by a hydroxy;

[0023] A is selected from

[0024] C₃-C₆ cycloalkyl, optionally substituted with a group selectedfrom hydroxy and (C₁-C₄)alkyl,

[0025] 5 to 10-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N, saidheterocyclyl being optionally substituted with a group selected from(C₁-C₄)alkyl and NR₉R₁₀ wherein R₉ and R₁₀ are the same or different andare selected from H and (C₁-C₄)alkyl or

[0026] a group

[0027]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo and trifluoromethyl whereinR₉ and R₁₀ are the same or different and are selected from H and(C₁-C₄)alkyl; or

[0028] b) wherein

[0029] Q is a single bond or a saturated 1 to 4 carbon atom chainoptionally substituted with a (C₁-C₄)alkyl;

[0030] R₁ and R₁′ are the same or different and are selected fromhydrogen and (C₁-C₄)alkyl provided that when R₁ and R₁′ are both C₁-C₄alkyl, they are identical;

[0031] ;

[0032] R₂ is benzyl optionally substituted with 1, 2 or 3 groupsselected from hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy,halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl and NR₉R₁₀wherein R₉ and R₁₀ are identical or different and are selected fromhydrogen and (C₁-C₄)alkyl;

[0033] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl optionally substituted by a hydroxy; and,

[0034] A is selected from

[0035] C₃-C₆ cycloalkyl, optionally substituted with a group selectedfrom hydroxy and (C₁-C₄)alkyl,

[0036] 5 to 6-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N, saidheterocyclyl being optionally substituted with a group selected from(C₁-C₄)alkyl and NR₉R₁₀ wherein R₉ and R₁₀ are the same or different andare selected from H and (C₁-C₄)alkyl or

[0037] a group

[0038]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo and trifluoromethyl whereinR₉ and R₁₀ are the same or different and are selected from H and(C₁-C₄)alkyl; or

[0039] c) wherein

[0040] Q is a single bond or a saturated 1 to 4 carbon atom chainoptionally substituted with a (C₁-C₄)alkyl;

[0041] R₁ and R₁′ are the same or different and are selected fromhydrogen and (C₁-C₄)alkyl provided that when R₁ and R₁′ are both C₁-C₄alkyl, they are identical;

[0042] R₂ is selected from hydrogen, (C₁-C₄)alkyl and benzyl optionallysubstituted with 1, 2 or 3 groups selected from hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl and NR₉R₁₀ wherein R₉ andR₁₀ are identical or different and are selected from hydrogen and(C₁-C₄)alkyl;

[0043] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl optionally substituted by a hydroxy; and,

[0044] A is selected from

[0045] C₃-C₆ cycloalkyl, optionally substituted with a group selectedfrom hydroxy and (C₁-C₄)alkyl,

[0046] 5 to 10-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N, saidheterocyclyl being optionally substituted with a group selected from(C₁-C₄)alkyl and NR₉R₁₀ wherein R₉ and R₁₀ are the same or different andare selected from H and (C₁-C₄)alkyl or

[0047] a group

[0048]  wherein one of R₄, R₅, R₆, R₇ and R₈ is selected from O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀ and NR₉R₁₀ and the others are eachindependently selected from the group consisting of hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo andtrifluoromethyl wherein R₉ and R₁₀ are the same or different and areselected from H and (C₁-C₄)alkyl;

[0049] or, if appropriate, their pharmaceutically acceptable saltsand/or isomers, tautomers, solvates or isotopic variations thereof.

[0050] In the present invention, the term “potent” means that thecompounds of formula (1) show an agonist potency for the β2 receptor,which is less than 10 nM as measured by the cell-based assay describedherein.

[0051] In the here above general formula (1), (C₁-C₄)alkyl radicalsdenote a straight-chain or branched group containing 1, 2, 3 or 4 carbonatoms and (C₁-C₆)alkyl radicals denote a straight-chain or branchedgroup containing 1, 2, 3, 4, 5 or 6 carbon atoms respectively. This alsoapplies if they carry substituents or occur as substituents of otherradicals, for example in (C₁-C₆)alkoxy radicals, hydroxy(C₁-C₆)alkylradicals, thio(C₁-C₆)alkyl radicals etc. . . . Examples of suitable(C₁-C₆)alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl,iso-hexyl, 3-methylpentyl etc. . . . Examples of suitable (C₁-C₆)alkoxyradicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy,iso-butyloxy, sec-butyloxy and tert-butyloxy, n-pentyloxy,iso-pentyloxy, tert-pentyloxy, n-hexyloxy, iso-hexyloxy,3-methylpentyloxy etc. . . . Hydroxy(C₁-C₆)alkyl radicals are alkylradicals substituted by a hydroxy group (—OH). According to a preferredembodiment of said invention, such radicals contain one hydroxysubstituent. Examples of suitable hydroxy(C₁-C₆)alkyl radicals arehydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl. Thio(C₁-C₆)alkylradicals are alkyl radicals attached to through a —S— atom, i.e.thio(C₁-C₆)alkyl means —S-alkyl. Examples of suitable thio(C₁-C₆)alkylradicals are thiomethyl, thioethyl, thiopropyl etc. . . .

[0052] The term C₃-C₆ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

[0053] Examples of suitable 5 to 10-membered aromatic heterocyclylcontaining from 1 to 3 heteroatoms selected from O, S or N are thienyl,furanyl, pyranyl, pyrrolyl, imidazolyl, imidazopyridine, pyrazolyl,thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidyl, pyridazyl, triazolyl, isobenzofuranyl,benzofuranyl, benzimidazolyl, benzthiazolyl, indolyl, iso-indolyl,indazolyl, isoquinolyl, quinolyl and naphthyridinyl.

[0054] Preferred 5 or 6-membered aromatic heterocyclyl containing from 1to 3 heteroatoms selected from O, S or N are thiazolyl, pyridyl.

[0055] In the general formula (1) according to the present invention,when a radical is mono- or poly-substituted, said substituent(s) can belocated at any desired position(s). Also, when a radical ispolysubstituted, said substituents can be identical or different.

[0056] Finally, halo denotes a halogen atom selected from the groupconsisting of fluoro, chloro, bromo and iodo in particular fluoro orchloro.

[0057] Preferably, R₁ is selected from methyl and ethyl. Morepreferably, R₁ is methyl.

[0058] Preferably, R₁′ is selected from H and methyl. More preferablyR₁′ is H.

[0059] Preferably, R₂ is selected from H, methyl, ethyl and benzyl.

[0060] Preferably, R₃ is selected from H and methyl, more preferably R₃is H.

[0061] Preferably, Q is selected from —CH₂—, CH₂—CH₂, and —CH(CH₃)—.

[0062] Preferably, when A is phenyl, at least 2 of R₄, R₅, R₆, R₇ and R₈are hydrogen.

[0063] Preferably, A is selected from C₃-C₆ cycloalkyl, 5 or 6-memberedaromatic heterocyclyl containing 1 or 2 heteroatoms selected from O, Sor N and a group

[0064] wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀, benzyloxy,hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,thio(C₁-C₆)alkyl, halo and trifluoromethyl wherein R₉ and R₁₀ are thesame or different and are selected from H and (C₁-C₄)alkyl;

[0065] Preferably, A is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, thiazolyl, pyridyl and a group

[0066] wherein 2 of R₄, R₅, R₆, R₇ and R₈ are hydrogen and the othersare selected from chloro, fluoro, methyl, hydroxy, methoxy, ethoxy,benzyloxy, trifluoromethyl, trifluoromethyloxy, thiomethyl and SO₂NR₉R₁₀wherein R₉ and R₁₀ are the same or different and are selected fromhydrogen or (C₁-C₄)alkyl

[0067] Preferred compounds according to the invention are compounds offormula (1)

[0068] a) wherein

[0069] Q is a saturated 1 to 4 carbon atom chain substituted with a(C₁-C₄)alkyl;

[0070] R₁ is (C₁-C₄)alkyl and R₁′ is H.

[0071] R₂ is selected from hydrogen, (C₁-C₄)alkyl and benzyl;

[0072] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl;

[0073] A is selected from

[0074] C₃-C₆ cycloalkyl,

[0075] 5 or 6-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N, and,

[0076] a group

[0077]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo and trifluoromethyl whereinR₉ and R₁₀ are the same or different and are selected from H and(C₁-C₄)alkyl; or

[0078] b) wherein

[0079] Q is a single bond or a saturated 1 to 4 carbon atom chainoptionally substituted with a (C₁-C₄)alkyl;

[0080] R₁ is selected from hydrogen and (C₁-C₄)alkyl and R₁′ is H;

[0081] R₂ is benzyl;

[0082] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl

[0083] A is selected from

[0084] C₃-C₆ cycloalkyl,

[0085] 5 or 6-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N, and,

[0086] a group

[0087]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo and trifluoromethyl whereinR₉ and R₁₀ are the same or different and are selected from H and(C₁-C₄)alkyl; or

[0088] c) wherein

[0089] Q is a single bond or a saturated 1 to 4 carbon atom chainoptionally substituted with a (C₁-C₄)alkyl;

[0090] R₁ is selected from hydrogen and (C₁-C₄)alkyl and R₁′ is H;

[0091] R₂ is selected from hydrogen, (C₁-C₄)alkyl and benzyl;

[0092] R₃ is selected from the group consisting of hydrogen and(C₁-C₆)alkyl

[0093] A is selected from

[0094] C₃-C₆ cycloalkyl;

[0095] 5 or 6-membered aromatic heterocyclyl containing from 1 to 3heteroatoms, identical or different, selected from O, S or N;

[0096] a group

[0097]  wherein one of R₄, R₅, R₆, R₇ and R₈ is selected from O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀ and NR₉R₁₀ and the others are eachindependently selected from the group consisting of hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo andtrifluoromethyl wherein R₉ and R₁₀ are the same or different and areselected from H and (C₁-C₄)alkyl;

[0098] or, if appropriate, their pharmaceutically acceptable saltsand/or isomers, tautomers, solvates or isotopic variations thereof.

[0099] Further preferred compounds according to the invention arecompounds of formula (1)

[0100] a) wherein

[0101] Q is —CH(CH₃)—;

[0102] R₁ is selected from methyl or ethyl and R₁′ is H;

[0103] R₂ is selected from hydrogen, methyl, ethyl and benzyl;

[0104] R₃ is selected from hydrogen and methyl;

[0105] A is selected from

[0106] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0107] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0108] a group

[0109]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀, benzyloxy,hydroxy, methyl, methoxy, ethoxy, thiomethyl, halo and trifluoromethylwherein R₉ and R₁₀ are the same or different and are selected fromhydrogen and methyl; or,

[0110] b) wherein

[0111] Q is selected from —CH₂—, CH₂—CH₂, and —CH(CH₃)—;

[0112] R₁ is selected from methyl or ethyl and R₁′ is H;

[0113] R₂ is benzyl;

[0114] R₃ is selected from hydrogen and methyl;

[0115] A is selected from

[0116] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0117] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0118] a group

[0119]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀, benzyloxy,hydroxy, methyl, methoxy, ethoxy, thiomethyl, halo and trifluoromethylwherein R₉ and R₁₀ are the same or different and are selected fromhydrogen and methyl; or

[0120] c) wherein

[0121] Q is selected from —CH₂—, CH₂—CH₂, and —CH(CH₃)—;

[0122] R₁ is selected from methyl or ethyl and R₁′ is H;

[0123] R₂ is selected from hydrogen, methyl, ethyl and benzyl;

[0124] R₃ is selected from hydrogen and methyl;

[0125] A is selected from

[0126] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0127] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0128] a group

[0129]  wherein one of R₄, R₅, R₆, R₇ and R₈ is selected from O—CF₃ andSO₂NR₉R₁₀ and the others are each independently selected from the groupconsisting of hydrogen, O—CF₃, SO₂NR₉R₁₀, benzyloxy, hydroxy, methyl,methoxy, ethoxy, thiomethyl, halo and trifluoromethyl wherein R₉ and R₁₀are the same or different and are selected from hydrogen and methyl.

[0130] More preferred compounds according to the invention are compoundsof formula (1)

[0131] a) wherein

[0132] Q is —CH(CH₃)—;

[0133] R₁ is selected from methyl or ethyl and R₁′ is H;

[0134] R₂ is selected from hydrogen, methyl, ethyl and benzyl;

[0135] R₃ is hydrogen;

[0136] A is selected from

[0137] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0138] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0139] a group

[0140]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀ and methoxywherein R₉ and R₁₀ are the same or different and are selected fromhydrogen and methyl; or,

[0141] b) wherein

[0142] Q is selected from —CH₂— and —CH(CH₃)—;

[0143] R₁ is selected from methyl or ethyl and R₁′ is H;

[0144] R₂ is benzyl;

[0145] R₃ is hydrogen;

[0146] A is selected from

[0147] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0148] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0149] a group

[0150]  wherein R₄, R₅, R₆, R₇ and R₈ are each independently selectedfrom the group consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀ and methoxywherein R₉ and R₁₀ are the same or different and are selected fromhydrogen and methyl; or,

[0151] c) wherein

[0152] Q is selected from —CH₂— and —CH(CH₃)—;

[0153] R, is selected from methyl or ethyl and R₁′ is H;

[0154] R₂ is selected from hydrogen, methyl, ethyl and benzyl;

[0155] R₃ is hydrogen;

[0156] A is selected from

[0157] C₃-C₆ cycloalkyl, preferably cyclopropyl, cyclopentyl orcyclohexyl;

[0158] 5 or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S or N, preferablypyridyl or thiazolyl and,

[0159] a group

[0160]  wherein one of R₄, R₅, R₆, R₇ and R₈ is selected from O—CF₃ andSO₂NR₉R₁₀ and the others are each independently selected from the groupconsisting of hydrogen, O—CF₃, SO₂NR₉R₁₀ and methoxy wherein R₉ and R₁₀are the same or different and are selected from hydrogen and methyl.

[0161] Particularly preferred are the indole derivatives of the formula(1) as described in the Examples section hereafter, i.e.:

[0162] 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-trifluoromethoxybenzyl)-1H-indole-2-carboxamide;

[0163] 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1S)-1-phenylethyl]-1H-indole-2-carboxamide;

[0164]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(3-trifluoromethoxyphenylethyl)-1H-indole-2-carboxamide;

[0165]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(pyridin-2-ylmethyl)-1H-indole-2-carboxamide;

[0166]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopropylmethyl)-1H-indole-2-carboxamide;

[0167]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide;

[0168]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(thiazol-2-ylmethyl)-1H-indole-2-carboxamide;

[0169]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclobutylmethyl)-1H-indole-2-carboxamide;

[0170]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopentylmethyl)-1H-indole-2-carboxamide;

[0171] 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclohexylmethyl)-1H-indole-2-carboxamide;

[0172]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-methylsulfamoylbenzyl)-1H-indole-2-carboxamide;

[0173]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-sulfamoylbenzyl)-1H-indole-2-carboxamide;

[0174]1-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-methoxybenzyl)-1H-indole-2-carboxamide;

[0175]1-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide;

[0176]1-Ethyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-2-phenylethyl)-1H-indole-2-carboxamide;

[0177]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl)-1-methyl-1H-indole-2-carboxamide;

[0178]1-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2,6-dimethoxybenzyl)-1H-indole-2-carboxamide,

[0179]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)butyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide,and,

[0180]5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)butyl}-N-[3-methyl-pyridin-2-ylmethyl]-1H-indole-2-carboxamide.

[0181] The indole derivatives of the formula (1) can be prepared usingconventional procedures such as by the following illustrative methods inwhich R₁, R₂, R₃, Q and A are as previously defined for the indolederivatives of the formula (1) unless otherwise stated.

[0182] The indole derivatives of the formula (1) may be prepared bycoupling an acid of formula (2):

[0183] with an amine of formula (3):

[0184] wherein R₃, Q and A are as previously defined. The coupling isgenerally carried out in an excess of said amine as an acid receptor,with a conventional coupling agent (e.g.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride orN,N′-dicyclohexylcarbodiimide), optionally in the presence of a catalyst(e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole),and optionally in the presence of a tertiary amine base (e.g.N-methylmorpholine, triethylamine or diisopropylethylamine). Thereaction may be undertaken in a suitable solvent such as pyridine,dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethaneor ethyl acetate, and at temperature comprised between 10° C. and 40° C.(room temperature). It may also be necessary to deprotect one of thesubstituents to furnish the desired compound. This may be achieved by,in the case of a benzyl protecting group, hydrogenation typically at15-60 psi in a solvent such as methanol or ethanol at ambient or up to50° C.

[0185] Said amine (3) is either commercially available or may beprepared by conventional methods well known to the one skilled in theart (e.g. reduction, oxidation, alkylation, protection, deprotectionetc. . . . ) from commercially available material.

[0186] The acid of formula (2) may be prepared from the correspondingester of formula (4):

[0187] wherein Ra is a suitable acid protecting group, preferably a(C₁-C₄)alkyl group, which includes, but is not limited to, methyl andethyl, according to any method well-known to the one skilled in the artto prepare an acid from an ester, without modifying the rest of themolecule. For example, the ester may be hydrolysed by treatment withaqueous acid or base (e.g. hydrogen chloride, potassium hydroxide,sodium hydroxide or lithium hydroxide), optionally in the presence of asolvent or mixture of solvents (e.g. water, 1,4-dioxan,tetrahydrofuran/water), at a temperature comprised between 20° C. and100° C., for a period of 1 to 40 hours.

[0188] The ester of formula (4) may be prepared by reaction of an amineof formula (5):

[0189] wherein Ra is as previously defined,

[0190] with a bromide of formula (6):

[0191] In a typical procedure, the amine of formula (5) is reacted witha bromide of formula (6) optionally in the presence of a solvent ormixture of solvents (e.g. dimethyl sulfoxide, toluene,N,N-dimethylformamide), optionally in the presence of a suitable base(e.g. triethylamine, diisopropylethylamine) at a temperature comprisedbetween 80° C. and 120° C., for 12 to 48 hours.

[0192] The bromide of formula (6) may be prepared from the ester offormula (7):

[0193] according to any method well-known to the one skilled in the artto prepare an alcohol from an ester, without modifying the rest of themolecule.

[0194] In a typical procedure, the ester of formula (7) is reduced withborane methylsulfide complex in tetrahydrofuran at a reflux for a periodof 2 hours.

[0195] The alcohol of formula (7) may be prepared as either the (R) or(S) enantiomer according to methods well described in the literature(Tetrahedron Letters 1994, 35(50), 9375).

[0196] The amine of formula (5) wherein R₁ and R₁′ are C₁-C₄ alkyl maybe prepared from the tertiary alcohol of formula (13).

[0197] Said tertiary alcohol of formula (13) is treated with an alkylnitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of anacid (e.g. sulphuric acid, acetic acid) to give a protected intermediatewhich in turn is cleaved using standard methodology for cleavingnitrogen protecting group such as those mentioned in textbooks, to givethe amine of formula (5) wherein R₁ and R₁′ are C₁-C₄ alkyl.

[0198] The tertiary alcohol of formula (13) may be prepared from theketone of formula (14):

[0199] In a typical procedure, the ketone of formula (14) is reactedwith an “activated” alkyl (organometallic alkyl such as R₁MgBr, R₁MgClor R¹Li) to give the corresponding tertiary alcohol of formula (13).This organometallic addition is generally undertaken in a suitablesolvent such as tetrahydrofuran, ether, cyclohexane or 1,4-dioxane, at atemperature comprised between 10° C. and 40° C. (room temperature) for 1to 24 hours

[0200] The amine of formula (5) wherein R₁′ is hydrogen may be preparedas either the (R) or (S) enantiomer from the corresponding protectedindole of formula (8):

[0201] wherein Ra is as previously defined and Rb and Rc represent anysuitable substituents so that HNRbRc is a chiral amine (for example, Rbmay be hydrogen and Rc may be a α-methylbenzyl group), provided that thebonds between N and Rb and N and Rc can be easily cleaved to give thefree amine of formula (5) using standard methodology for cleavingnitrogen protecting groups, such as that found in the text book (see forexample T. W. GREENE, Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981).

[0202] The amine of formula (8) as either (R) or (S) enantiomer may beprepared by alkylation of a compound of formula (9):

[0203] wherein R₁, Ra, Rb and Rc are as previously defined.

[0204] In a typical procedure, the compound of formula (9) may bealkylated with a suitable alkylating agent (e.g. R₂Br or R₂I) in thepresence of a suitable base (e.g. sodium hydride). The reaction isgenerally done in a solvent such as tetrahydrofuran ordimethylformamide, at a temperature comprised between-10° C. and 80° C.for 1 to 16 hours. The product is then converted to the hydrochloridesalt and selectively crystallised from a suitable solvent or mixture ofsolvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether ordiisopropyl ether/methanol) to give the chiral product of formula (8) orits enantiomer if the opposite enantiomer of the amine NHRbRc is used.

[0205] The compound of formula (9) may be prepared by reaction of anamine of formula HNRbRc with a ketone of formula (10):

[0206] wherein R₁, Ra, Rb and Rc are as previously defined.

[0207] In a typical procedure, the reaction of the ketone of formula(10) with the amine of formula HNRbRc leads to a chiral intermediatewhich is in turn reduced by a suitable reducing agent (e.g. sodiumcyanoborohydride of formula NaCNBH₃ or sodium triacetoxyborohydride offormula Na(OAc)₃BH) optionally in the presence of a drying agent (e.g.molecular sieves, magnesium sulfate) and optionally in the presence ofan acid catalyst (e.g. acetic acid) to give the amine of formula (9).The reaction is generally done in a solvent such as tetrahydrofuran ordichloromethane at a temperature comprised between 20° C. and 80° C. for3 to 72 hours.

[0208] The ketone of formula (10) may be prepared by palladium mediatedcoupling of an aryl halide of formula (11):

[0209] wherein Ra is as previously defined and Hal represents an halogenatom, which includes, but is not limited to bromo and iodo, with anenolate or enolate equivalent.

[0210] In a typical procedure, the aryl halide of formula (11) isreacted with a tin enolate generated in-situ by treatment of isoprenylacetate with tri-n-butyltin methoxide of formula Bu₃SnOMe in thepresence of a suitable palladium catalyst (palladiumacetate/tri-ortho-tolylphosphine of formula Pd(OAc)₂/P(o-Tol)₃) in anon-polar solvent (e.g. toluene, benzene, hexane). Preferably, thereaction is carried out at a temperature comprised between 80° C. and110° C. for 6 to 16 hours.

[0211] The aryl halide of formula (11) may be obtained by esterificationof the corresponding acid of formula (12):

[0212] wherein Hal is as previously defined, according to any methodwell-known to the one skilled in the art to prepare an ester from anacid, without modifying the rest of the molecule.

[0213] In a typical procedure, the acid of formula (12) is reacted withan alcoholic solvent of formula RaOH, wherein Ra is as previouslydefined, in the presence of an acid such as hydrogen chloride at atemperature between 10° C. and 40° C. (room temperature) for 8 to 16hours.

[0214] The acid of formula (12) is a commercial product. The inventionalso relates to an intermediate of formula (2):

[0215] wherein R₁ and R₁′ are the same or different and are selectedfrom hydrogen and (C₁-C₄)alkyl and R₂ is benzyl optionally substitutedwith 1, 2 or 3 groups selected from hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl and NR₉R₁₀ wherein R₉ and R₁₀ are identical or differentand are selected from hydrogen and (C₁-C₄)alkyl. The invention alsorelates to an intermediate of formula (4):

[0216] wherein R₁ and R₁′ are the same or different and are selectedfrom hydrogen and (C₁-C₄)alkyl, R₂ is benzyl optionally substituted with1, 2 or 3 groups selected from hydroxy, methoxy, (C₁-C₄)alkyl and NR₉R₁₀wherein R₉ and R₁₀ are identical or different and are selected fromhydrogen and (C₁-C₄)alkyl, and Ra is a suitable acid protecting groupselected from (C₁-C₄)alkyl groups.

[0217] All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well-knownto those skilled in the art with reference to literature precedents andthe examples and preparations hereto.

[0218] For some of the steps of the here above described process ofpreparation of the indole derivatives of formula (1), it can benecessary to protect the potential reactive functions that are notwished to react, and to cleave said protecting groups in consequence. Insuch a case, any compatible protecting radical can be used. Inparticular methods of protection and deprotection such as thosedescribed by T. W. GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protectinggroups, Georg Thieme Verlag, 1994), can be used.

[0219] Also, the indole derivatives of formula (1) as well asintermediate for the preparation thereof can be purified according tovarious well-known methods, such as for example crystallization orchromatography.

[0220] The indole derivatives of formula (1) may also be optionallytransformed into pharmaceutically acceptable salts. In particular, thesepharmaceutically acceptable salts of the indole derivatives of theformula (1) include the acid addition and the base salts thereof.

[0221] Suitable acid addition salts are formed from mineral or organicnon-toxic acids which form non-toxic salts. Suitable examples of theseacid addition salts are the hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate,maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate,saccharate, benzoate, methanesulphonate, ethanesulphonate,benzenesulphonate, p-toluenesulphonate, pamoate and xinafoate salts.

[0222] Suitable base salts are formed from bases, which form non-toxicsalts, such as alkali metal salts, earth metal salts or addition saltswith ammonia and physiologically tolerable organic amines. Suitableexamples of these base salts are the sodium, potassium, aluminium,calcium, magnesium, zinc or ammonium salts as well as addition saltswith triethylamine, ethanolamine, diethanolamine, trimethylamine,methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine,benzylamine, dicyclohexylamine, N-benzyl-β-phenethylamine,N,N′-dibenzylethylenediamine, diphenylenediamine, quinine, choline,arginine, lysine, leucine, dibenzylamine, tris(2-hydroxyethyl)amine, orα,α,α-tris(hydroxymethyl)methylamine.

[0223] Compounds which contain both acidic groups and basic groups canalso be present in the form of internal salts or betaines, which arealso included by the present invention. For a review on suitable saltssee Berge et al., J. Pharm. Sci., 1977, 66, p. 1-19.

[0224] Salts can generally be obtained from the indole derivatives ofthe formula (1) according to customary procedures known to the personskilled in the art, for example by combining with an organic orinorganic acid or base solvent or dispersant, or alternatively fromother salts by anion exchange or cation exchange. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent.

[0225] The indole derivatives of the formula (1) can also be present instereoisomeric forms. If the indole derivatives of the formula (1)contain one or more centres of asymmetry, these can independently of oneanother have the (S) configuration or the (R) configuration. Theinvention includes all possible stereoisomers of the indole derivativesof the formula (1), for example enantiomers and diastereomers, andmixtures of two or more stereoisomeric forms, for example mixtures ofenantiomers and/or diastereomers, in all ratios. The invention thusrelates to enantiomers in enantiomerically pure form, both aslevorotatory and dextrorotatory antipodes, in the form of racemates andin the form of mixtures of the two enantiomers in all ratios. Theinvention likewise relates to diastereomers in diastereomerically pureform and in the form of mixtures in all ratios. In the presence ofcis/trans isomerism, the invention relates to both the cis form and thetrans form and mixtures of these forms in all ratios. Individualstereoisomers can be prepared, if desired, by use of stereochemicallyhomogeneous starting substances in the synthesis, by stereoselectivesynthesis or by separation of a mixture according to customary methods,for example by chromatography, crystallization or by chromatography onchiral phases. If appropriate, derivatization can be carried out beforeseparation of stereoisomers. A stereoisomer mixture can be separated atthe stage of the indole derivatives of the formula (1) or at the stageof a starting substance or of an intermediate in the course of thesynthesis.

[0226] According to one aspect of the present invention, the(R,R)-stereoisomer is generally preferred.

[0227] The compounds of the formula (1) according to the invention canmoreover contain mobile hydrogen atoms, i.e. be present in varioustautomeric forms. The present invention also relates to all tautomers ofthe compounds of the formula (1).

[0228] The present invention furthermore includes other types ofderivatives of indole derivatives of the formula (1), for example,solvates such as hydrates and polymorphs, i.e. the various differentcrystalline structures of the indole derivatives according to thepresent invention.

[0229] The present invention also includes all suitable isotopicvariations of the indole derivatives of the formula (1) or apharmaceutically acceptable salt thereof. An isotopic variation of theindole derivatives of the formula (1) or a pharmaceutically acceptablesalt thereof is defined as one in which at least one atom is replaced byan atom having the same atomic number but an atomic mass different fromthe atomic mass usually found in nature. Examples of isotopes that canbe incorporated into the indole derivatives of the formula (1) andpharmaceutically acceptable salts thereof include isotopes of hydrogen,carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the indole derivatives of the formula (1) andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e. ³H,and carbon-14, i.e. ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e. H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of the indolederivatives of the formula (1) and pharmaceutically acceptable saltsthereof of this invention can generally be prepared by conventionalprocedures such as by the illustrative methods or by the preparationsdescribed in the Examples and Preparations sections hereafter usingappropriate isotopic variations of suitable reagents.

[0230] According to a further aspect, the present invention concernsmixtures of indole derivatives of the formula (1), as well as mixtureswith or of their pharmaceutically acceptable salts, solvates, isomericforms and/or isotope forms.

[0231] According to the present invention, all the here above mentionedforms of the indole derivatives of formula (1) except thepharmaceutically acceptable salts (i.e. said solvates, isomeric forms,tautomers and isotope forms), are defined as “derived forms” of theindole derivatives of formula (1) in what follows (including theclaims).

[0232] The indole derivatives of formula (1), their pharmaceuticallyacceptable salts and/or derived forms, are valuable pharmaceuticallyactive compounds, which are suitable for the therapy and prophylaxis ofnumerous disorders in which the β2 receptor is involved or in whichagonism of this receptor may induce benefit, in particular the allergicand non-allergic airways diseases but also in the treatment of otherdiseases such as, but not limited to those of the nervous system,premature labor, congestive heart failure, depression, inflammatory andallergic skin diseases, psoriasis, proliferative skin diseases, glaucomaand in conditions where there is an advantage in lowering gastricacidity, particularly in gastric and peptic ulceration.

[0233] The indole derivatives of formula (1) and their pharmaceuticallyacceptable salts and derived forms as mentioned above can beadministered according to the invention to animals, preferably tomammals, and in particular to humans, as pharmaceuticals for therapyand/or prophylaxis. They can be administered per se, in mixtures withone another or in the form of pharmaceutical preparations which asactive constituent contain an efficacious dose of at least one indolederivative of the formula (1), its pharmaceutically acceptable saltsand/or derived forms, in addition to customary pharmaceuticallyinnocuous excipients and/or additives.

[0234] Thus, the present invention also relates to compositionscontaining an indole derivative of formula (1) and/or theirpharmaceutically acceptable salts and/or derived forms, together withcustomary pharmaceutically innocuous excipients and/or additives. Suchcompositions are prepared according to well-known methods compatiblewith the standard pharmaceutical practice. Said compositions generallycontain from 0.5% to 60% in weight of the active compound and from 40%to 99.5% in weight of excipients and/or additives. According to thepresent invention, said excipients and/or additives are agents wellknown to the artisan for providing favourable properties in the finalpharmaceutical composition. Typical excipients and/or additives include,but are by no means limited to, acidifying and alkalizing agents,aerosol propellants, anti-microbial agents (including anti-bacterial,anti-fungal and anti-protozoal agents), antioxidants, buffering agents,chelating agents, dispersing agents, suspending agents, emollients,emulsifying agents, preservatives, sequestering agents, solvents,stabilizers, stiffening agents, sugars, surfactants and flavouringagents. Furthermore, said compositions are prepared in a form compatiblefor the intended route of administration, which is used for any givenpatient, as well as appropriate to the disease, disorder or conditionfor which any given patient is being treated. Suitable routes ofadministration that can be envisaged are for example the topical, oral,inhaled, rectal, intra-veinous, intra-arterial, intra-peritoneal,intra-thecal, intra-ventricular, intra-urethral, intra-sternal,intra-cranial, intramuscular, subcutaneous or ocular routes. In thepresent case, the inhalation route is preferred.

[0235] When an administration by the oral route is intended, the indolederivatives of formula (1), their pharmaceutically acceptable saltsand/or their derived forms, can be administered in the form of tablets,capsules, multi-particulates, gels, films, ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications. The indole derivatives of formula (1),their pharmaceutically acceptable salts and/or their derived forms, mayalso be administered as fast-dispersing or fast-dissolving dosage formsor in the form of a high energy dispersion or as coated particles.Suitable formulations of the indole derivatives of formula (1), theirpharmaceutically acceptable salts and/or their derived forms, may be incoated or uncoated form, as desired.

[0236] Such solid pharmaceutical compositions, for example, tablets, maycontain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate, glycine andstarch (preferably corn, potato or tapioca starch), disintegrants suchas sodium starch glycollate, croscarmellose sodium and certain complexsilicates, and granulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

[0237] As a general example, a formulation of the tablet could typicallycontain between about 0.001 mg and 5000 mg of active compound whilsttablet fill weights may range from 50 mg to 5000 mg. The tablets may bemanufactured by a standard process, for example by direct compression orby a wet or dry granulation process. The tablet cores may be coated withappropriate overcoats.

[0238] Solid compositions of a similar type may also be employed asfillers in gelatin or HPMC capsules. Preferred excipients in this regardinclude lactose, starch, a cellulose, milk sugar or high molecularweight polyethylene glycols. For aqueous suspensions and/or elixirs, theindole derivatives of the formula (1), their pharmaceutically acceptablesalts and/or their derived forms, may be combined with varioussweetening or flavouring agents, colouring matter or dyes, withemulsifying and/or suspending agents and with diluents such as water,ethanol, propylene glycol and glycerin, and combinations thereof.

[0239] The indole derivatives of the formula (1), their pharmaceuticallyacceptable salts and/or their derived forms, can also be administered byinjection, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion or needleless injection techniques.For such administration they are best used in the form of a sterileaqueous solution which may contain other substances, for example, enoughsalts or glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of such formulations under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art.

[0240] For both oral administration and injection to human patients, thedaily dosage level of the indole derivatives of the formula (1), theirpharmaceutically acceptable salts and/or their derived forms, willusually be from 0.001 mg/kg to 1000 mg/kg (in single or divided doses).

[0241] The indole derivatives of the formula (1), their pharmaceuticallyacceptable salts and/or their derived forms, can also be administered byinhalation and are conveniently delivered in the form of a dry powderinhaler or an aerosol spray presentation from a pressurised container,pump, spray, atomiser or nebuliser, with or without the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A™) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA™), carbon dioxide or othersuitable gas. In the case of a pressurised aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Thepressurised container, pump, spray, atomiser or nebuliser may contain asolution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of an indole derivative of theformula (1) and a suitable powder base such as lactose or starch.

[0242] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 0.001 mg to 10 mg of anindole derivative of the formula (1) for delivery to the patient. Theoverall daily dose with an aerosol will be in the range of from 0.001 mgto 40 mg, which may be administered in a single dose or, more usually,in divided doses throughout the day.

[0243] The indole derivatives of the formula (1), their pharmaceuticallyacceptable salts and/or their derived forms, can also be administeredtopically, or transdermally, in the form of creams, gels, suspensions,lotions, ointments, dusting powders, sprays, foams, mousses,drug-incorporated dressings, solutions, sponges, fibres, microemulsions,films, skin patches, ointments such as petrolatum or white soft paraffinbased ointments or via a skin patch or other device. Penetrationenhancers may be used, and the compound may be used in combination withcyclodextrins. In addition, the compound may be delivered usingiontophoresis, electropration, phonophoresis or sonophoresis. They couldbe administered directly onto a wound site. They could be incorporatedinto a coated suture. For example they can be incorporated into a lotionor cream consisting of an aqueous or oily emulsion of mineral oils,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol, water, polyethylene glycolsand/or liquid paraffin, or they can be incorporated into a suitableointment consisting of one or more of the following: mineral oil, liquidpetrolatum, white petrolatum, propylene glycol, polyoxyethylenepolyoxypropylene compound, emulsifying wax and water, or as hydrogelwith cellulose or polyacrylate derivatives or other viscosity modifiers,or as a dry powder or liquid spray or aerosol with butane/propane, HFA,CFC, CO₂ or other suitable propellant, optionally also including alubricant such as sorbitan trioleate, or as a drug-incorporated dressingeither as a tulle dressing, with white soft paraffin or polyethyleneglycols impregnated gauze dressings or with hydrogel, hydrocolloid,alginate or film dressings.

[0244] For topical administration to human patients with acute/surgicalwounds or scars, the daily dosage level of the compounds, in suspensionor other formulation, could be from 0.001 to 50 mg/ml, preferably from0.03 to 30 mg/ml. The dosage will vary with the size of the wound,whether or not the wound is open or closed or partially closed, andwhether or not the skin is intact.

[0245] Alternatively, the indole derivatives of the formula (1), theirpharmaceutically acceptable salts and/or their derived forms, can berectally administered, for example in the form of a suppository of agel, although other forms can be considered.

[0246] They may also be administered by the ocular route, in particularfor ocular scarring. For ophthalmic use, the compounds can be formulatedas micronised suspensions in isotonic, pH adjusted, sterile saline, or,preferably, as solutions in isotonic, pH adjusted, sterile saline,optionally in combination with a preservative such as a benzylalkoniumchloride. Alternatively, they may be formulated in an ointment such aspetrolatum.

[0247] The various pharmaceutical formulations as decribed here aboveare also detailed in “Pharmacie galenique” from A. Lehir (Ed. Mason,1992, 2^(nd) edition).

[0248] The physician in any event will determine the actual dosage whichwill be most suitable for any individual patient and it will vary withthe age, weight, health state and sex of the patient as well as theseverity of the disease, disorder or condition to treat, the optionalcombination with other treatment(s), the response of the particularpatient and in general any factor peculiar to the concerned disease,disorder or condition and to the patient. Thus, the daily dose in humanmay usually contain from 0.001 mg to 5000 mg of active compound foradministration singly or two or more at a time, as appropriate. Therecan, of course, be individual instances where higher or lower dosageranges are merited and such are within the scope of this invention.

[0249] According to the present invention, the indole derivatives of theformula (1), their pharmaceutically acceptable salts and/or theirderived forms, may also be used in combination with a cyclodextrin.Cyclodextrins are known to form inclusion and non-inclusion complexeswith drug molecules. Formation of a drug-cyclodextrin complex may modifythe solubility, dissolution rate, bioavailability and/or stabilityproperty of a drug molecule. Drug-cyclodextrin complexes are generallyuseful for most dosage forms and administration routes. As analternative to direct complexation with the drug the cyclodextrin may beused as an auxiliary additive, e.g. as a carrier, diluent orsolubiliser. α-, β- and γ-cyclodextrins are most commonly used andsuitable examples are described in WO-A-91/11172, WO-A-94/02518 andWO-A-98/55148.

[0250] According to another embodiment of the present invention, theindole derivatives of the formula (1), or pharmaceutically acceptablesalts, derived forms or compositions thereof, can also be used as acombination with one or more additional therapeutic agents to beco-administered to a patient to obtain some particularly desiredtherapeutic end result. The second and more additional therapeuticagents may also be an indole derivative of the formula (1), orpharmaceutically acceptable salts, derived forms or compositionsthereof, or one or more β2 agonists known in the art. More typically,the second and more therapeutic agents will be selected from a differentclass of therapeutic agents.

[0251] As used herein, the terms “co-administration”, “co-administered”and “in combination with”, referring to the indole derivatives offormula (1) and one or more other therapeutic agents, is intended tomean, and does refer to and include the following:

[0252] simultaneous administration of such combination of indolederivative(s) and therapeutic agent(s) to a patient in need oftreatment, when such components are formulated together into a singledosage form which releases said components at substantially the sametime to said patient,

[0253] substantially simultaneous administration of such combination ofindole derivative(s) and therapeutic agent(s) to a patient in need oftreatment, when such components are formulated apart from each otherinto separate dosage forms which are taken at substantially the sametime by said patient, whereupon said components are released atsubstantially the same time to said patient, sequential administrationof such combination of indole derivative(s) and therapeutic agent(s) toa patient in need of treatment, when such components are formulatedapart from each other into separate dosage forms which are taken atconsecutive times by said patient with a significant time intervalbetween each administration, whereupon said components are released atsubstantially different times to said patient; and

[0254] sequential administration of such combination of indolederivative(s) and therapeutic agent(s) to a patient in need oftreatment, when such components are formulated together into a singledosage form which releases said components in a controlled mannerwhereupon they are concurrently, consecutively, and/or overlapinglyadministered at the same and/or different times by said patient, whereeach part may be administered by either the same or different route.

[0255] Suitable examples of other therapeutic agents which may be usedin combination with the indole derivatives of the formula (1), orpharmaceutically acceptable salts, derived forms or compositionsthereof, include, but are by no means limited to:

[0256] (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activatingprotein (FLAP) antagonists,

[0257] (b) Leukotriene antagonists (LTRAs) including antagonists ofLTB₄, LTC₄, LTD₄, and LTE₄,

[0258] (c) Histamine receptor antagonists including H1 and H3antagonists,

[0259] (d) α₁- and α₂-adrenoceptor agonist vasoconstrictorsympathomimetic agents for decongestant use,

[0260] (e) muscarinic M3 receptor antagonists or anticholinergic agents,

[0261] (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,

[0262] (g) Theophylline,

[0263] (h) Sodium cromoglycate,

[0264] (i) COX inhibitors both non-selective and selective COX-1 orCOX-2 inhibitors (NSAIDs),

[0265] (o) Oral and inhaled glucocorticosteroids,

[0266] (k) Monoclonal antibodies active against endogenous inflammatoryentities, (I) Anti-tumor necrosis factor (anti-TNF-α) agents,

[0267] (m) Adhesion molecule inhibitors including VLA-4 antagonists,

[0268] (n) Kinin-B₁- and B₂-receptor antagonists,

[0269] (o) Immunosuppressive agents,

[0270] (p) Inhibitors of matrix metalloproteases (MMPs),

[0271] (q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,

[0272] (r) Elastase inhibitors,

[0273] (s) Adenosine A2a receptor agonists,

[0274] (t) Inhibitors of urokinase,

[0275] (u) Compounds that act on dopamine receptors, e.g. D2 agonists,

[0276] (v) Modulators of the NFκβ pathway, e.g. IKK inhibitors,

[0277] (w) Agents that can be classed as mucolytics or anti-tussive, and

[0278] (x) Antibiotics.

[0279] According to the present invention, combination of the indolederivatives of formula (1) with:

[0280] glucocorticosteroids, in particular inhaled glucocorticosteroidswith reduced systemic side effects, including ciclesonide, prednisone,prednisolone, flunisolide, triamcinolone acetonide, beclomethasonedipropionate, budesonide, fluticasone propionate, and mometasonefuroate, or

[0281] muscarinic M3 receptor antagonists or anticholinergic agentsincluding in particular ipratropium salts, namely bromide, tiotropiumsalts, namely bromide, oxitropium salts, namely bromide, perenzepine,and telenzepine,

[0282] are preferred.

[0283] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment. Thedescription, which follows, concerns the therapeutic applications towhich the indole derivatives of formula (1) may be put.

[0284] The indole derivatives of formula (1) have the ability tointeract with the β2 receptor and thereby have a wide range oftherapeutic applications, as described further below, because of theessential role which the β2 receptor plays in the physiology of allmammals.

[0285] Therefore, a further aspect of the present invention relates tothe indole derivatives of formula (1), or pharmaceutically acceptablesalts, derived forms or compositions thereof, for use in the treatmentof diseases, disorders, and conditions in which the β2 receptor isinvolved. More specifically, the present invention also concerns theindole derivatives of formula (1), or pharmaceutically acceptable salts,derived forms or compositions thereof, for use in the treatment ofdiseases, disorders, and conditions selected from the group consistingof:

[0286] asthma of whatever type, etiology, or pathogenesis, in particularasthma that is a member selected from the group consisting of atopicasthma, non-atopic asthma, allergic asthma, atopic bronchialIgE-mediated asthma, bronchial asthma, essential asthma, true asthma,intrinsic asthma caused by pathophysiologic disturbances, extrinsicasthma caused by environmental factors, essential asthma of unknown orinapparent cause, non-atopic asthma, bronchitic asthma, emphysematousasthma, exercise-induced asthma, allergen induced asthma, cold airinduced asthma, occupational asthma, infective asthma caused bybacterial, fungal, protozoal, or viral infection, non-allergic asthma,incipient asthma, wheezy infant syndrome and bronchiolytis,

[0287] chronic or acute bronchoconstriction, chronic bronchitis, smallairways obstruction, and emphysema,

[0288] obstructive or inflammatory airways diseases of whatever type,etiology, or pathogenesis, in particular an obstructive or inflammatoryairways disease that is a member selected from the group consisting ofchronic eosinophilic pneumonia, chronic obstructive pulmonary disease(COPD), COPD that includes chronic bronchitis, pulmonary emphysema ordyspnea associated or not associated with COPD, COPD that ischaracterized by irreversible, progressive airways obstruction, adultrespiratory distress syndrome (ARDS), exacerbation of airwayshyper-reactivity consequent to other drug therapy and airways diseasethat is associated with pulmonary hypertension,

[0289] pneumoconiosis of whatever type, etiology, or pathogenesis, inparticular pneumoconiosis that is a member selected from the groupconsisting of aluminosis or bauxite workers' disease, anthracosis orminers' asthma, asbestosis or steam-fitters' asthma, chalicosis or flintdisease, ptilosis caused by inhaling the dust from ostrich feathers,siderosis caused by the inhalation of iron particles, silicosis orgrinders' disease, byssinosis or cotton-dust asthma and talcpneumoconiosis;

[0290] bronchitis of whatever type, etiology, or pathogenesis, inparticular bronchitis that is a member selected from the groupconsisting of acute bronchitis, acute laryngotracheal bronchitis,arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, drybronchitis, infectious asthmatic bronchitis, productive bronchitis,staphylococcus or streptococcal bronchitis and vesicular bronchitis,

[0291] bronchiectasis of whatever type, etiology, or pathogenesis, inparticular bronchiectasis that is a member selected from the groupconsisting of cylindric bronchiectasis, sacculated bronchiectasis,fusiform bronchiectasis, capillary bronchiectasis, cysticbronchiectasis, dry bronchiectasis and follicular bronchiectasis,

[0292] central nervous system disorders of whatever type, etiology, orpathogenesis, in particular a central nervous system disorder that is amember selected from the group consisting of depression, Alzheimersdisease, Parkinson's disease, learning and memory impairment, tardivedyskinesia, drug dependence, arteriosclerotic dementia and dementiasthat accompany Huntington's chorea, Wilson's disease, paralysis agitans,and thalamic atrophies,

[0293] premature labor, and

[0294] other type of diseases and conditions such as congestive heartfailure, depression, inflammatory and allergic skin diseases, psoriasis,proliferative skin diseases, glaucoma and conditions where there is anadvantage in lowering gastric acidity, particularly in gastric andpeptic ulceration.

[0295] A still further aspect of the present invention also relates tothe use of the indole derivatives of formula (1), or pharmaceuticallyacceptable salts, derived forms or compositions thereof, for themanufacture of a drug having a β2 agonist activity. In particular, thepresent inventions concerns the use of the indole derivatives of formula(1), or pharmaceutically acceptable salts, derived forms or compositionsthereof, for the manufacture of a drug for the treatment of β2-mediateddiseases and/or conditions, in particular the diseases and/or conditionslisted above.

[0296] As a consequence, the present invention provides a particularlyinteresting method of treatment of a mammal, including a human being,including treating said mammal with an effective amount of an indolederivative of formula (1), or a pharmaceutically acceptable salt,derived form or composition thereof. More precisely, the presentinvention provides a particularly interesting method of treatment of amammal, including a human being, to treat a β2-mediated diseases and/orconditions, in particular the diseases and/or conditions listed above,including treating said mammal with an effective amount of an indolederivative of formula (1), its pharmaceutically acceptable salts and/orderived forms.

[0297] The following examples illustrate the preparation of the indolederivatives of the formula (1):

[0298] Abbreviations:

[0299] DMF N,N-dimethylformamide

[0300] HOBt 1-hydroxybenzotriazole

[0301] WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0302] MeOH methanol

[0303] THF tetrahydrofuran

[0304] DIPEA diisopropylethylamine

[0305] EtOH ethanol

[0306] Et₂O diethylether

EXAMPLE 1 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-trifluoromethoxybenzyl)-1H-indole-2-carboxamide

[0307]

[0308] The acid from Preparation 6 (145 m g, 292 μmol) in DMF (1 ml) wastreated with 2-trifluoromethoxybenzylamine (57 mg, 301 μmol), pyridine(26 mg, 325 μmol), HOBt (43 mg, 320 μmol) in DMF (1 ml) and WSCDI (62mg, 322 μmol) in DMF (1 ml) and the mixture shaken overnight. Thesolvent was removed in vacuo and replaced with CH₂Cl₂ (2 ml) and water(0.5 ml). The organic phase was separated using a PTFE frit cartridgeand the solvent removed in vacuo. Ammonium fluoride (108 mg, 292 μmol)in MeOH (1.9 ml) and water (1.1 ml) was added to the crude material andthe mixture shaken at 40° C. overnight. The solvent was removed in vacuoand the crude material taken up in DMSO (1 ml) and filtered before beingpurified by reverse phase HPLC.

[0309]¹H NMR (400 MHz, CD₃OD): δ 7.52-7.44 (3H, m), 7.40-7.31 (4H, m),7.13 (3H, m), 6.77 (1H, d), 4.89 (1H, under solvent peak), 4.68 (2H, s),4.65 (2H, s), 3.60 (1H, m), 3.28-3.138 (3H, m), 2.86 (1H, m), 1.28 (3H,d).

[0310] HRMS (ESI): m/z [M+H]⁺ found 558.2188; requires 558.2217.

EXAMPLE 25-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1S)-1-phenylethyl]-1H-indole-2-carboxamide

[0311]

[0312] Prepared using the acid from Preparation 6 and the methoddescribed for Example 1.

[0313]¹H NMR (400 MHz, CD₃OD): contains ˜23% of the benzylamine δ 7.52(1H, s), 7.42 (3H, t), 7.34-7.29 (4H, m), 7.24 (1H, m), 7.13 (2H, t),6.77 (1H, d), 5.26 (1H, q), 4.88 (1H, under solvent peak), 4.65 (2H, s),3.59 (1H, m), 3.27-3.12 (3H, m), 2.86 (1H, m), 1.58 (3H, d), 1.27 (3H,d).

[0314] HRMS (ESI): m/z [M+H]⁺ found 488.2528; requires 488.2551.

EXAMPLE 35-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(3-trifluoromethoxyphenylethyl)-1H-indole-2-carboxamide

[0315]

[0316] Prepared using the acid from Preparation 6 and the methoddescribed for Example 1.

[0317]¹H NMR (400 MHz, CD₃OD): δ 7.52 (1H, s), 7.46-.7.41 (2H, m), 7.36(2H, m), 7.28 (1H, s), 7.15 (3H, m), 7.09 (1H, s), 6.78 (1H, d), 4.88(1H, under solvent peak), 4.65 (2H, s), 4.62 (2H, s), 3.63-3.54 (1H, m),3.28-3.13 (3H, m), 2.85 (1H, m), 1.27 (3H, d).

[0318] HRMS (ESI): m/z [M+H]⁺ found 558.2189; requires 558.2217.

EXAMPLE 45-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(pyridin-2-ylmethyl)-1H-indole-2-carboxamide

[0319]

[0320] Prepared using the acid from Preparation 6 and the methoddescribed for Example 1.

[0321]¹H NMR (400 MHz, CD₃OD): δ 8.50 (1H, d), 7.80 (1H, m), 7.48 (1H,d), 7.36-7.29 (3H, m), 7.16 (1H, m), 7.06 (1H, s), 7.02-6.94 (2H, m),6.59 (1H, d), 4.71 (2H, s), 4.60 (1H, m), 4.56 (2H, s), 2.79-2.68 (3H,m), 3.02-2.91 (2H, m), 1.12 (3H, d).

[0322] HRMS (ESI): m/z [M+H]⁺ found 475.2324; requires 475.2347.

EXAMPLE 55-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopropylmethyl)-1H-indole-2-carboxamide

[0323]

[0324] Prepared using the acid from Preparation 6 and the methoddescribed for Example 1.

[0325]¹H NMR (400 MHz, CD₃OD): δ 7.51 (1H, s), 7.43 (1H, d), 7.34 (1H,s), 7.13 (2H, m), 7.06 (1H, s), 6.77 (1H, d), 4.89 (1H, under solventpeak), 4.65 (2H, s), 3.62-3.55 (1H, m), 3.25-3.13 (5H, m), 2.85 (1H, m),1.26 (3H, d), 1.10 (1H, m), 0.53 (2H, m), 0.30 (2H, m).

[0326] HRMS (ESI): m/z [M+H]⁺ found 438.2327; requires 438.2394.

EXAMPLE 65-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide

[0327]

[0328] A solution of Preparation 5 (240 mg, 399 μmol) in a mixture ofmethanol (14 ml) and water (8 ml) was treated with ammonium fluoride(148 mg, 3.99 mmol) and the resulting suspension heated at 40° C.overnight. The solvent was removed in vacuo and the residue purified byflash chromatography [5 (+0.5% NH₃)−10% (+1.5% NH₃) MeOH in CH₂Cl₂] togive a white solid (82 mg).

[0329]¹H NMR (400 MHz, CD₃OD): δ 7.42 (2H, m), 7.33 (4H, m), 7.23 (1H,t), 7.17 (1H, s), 7.09 (1H, s), 7.00-6.94 (2H, m), 6.59 (1H, d), 5.25(1H, q), 4.58 (1H, m), 4.55 (2H, s), 2.99-2.89 (2H, m), 2.77-2.67 (3H,m), 1.59 (3H, d), 1.10 (3H, d).

[0330] LRMS (APCI): m/z [M+H]+488 [M+H]⁺.

EXAMPLE 75-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(thiazol-2-ylmethyl)-1H-indole-2-carboxamide

[0331]

[0332] Prepared using the amide from Preparation 4 and the methoddescribed for Example 6.

[0333]¹H NMR (400 MHz, CD₃OD): δ 7.72 (1H, d), 7.51 (1H, d), 7.36 (2H,m), 7.20 (1H, s), 6.98-7.05 (3H, m), 6.63 (1H, d), 4.88 (2H, s), 4.64(1H, m), 4.57 (2H, s), 3.06-3.11 (1H, m), 2.95 (1H, m), 2.69-2.87 (3H,m), 1.13 (3H, d).

[0334] HRMS (ESI): m/z [M+H]⁺ found 481.1901; requires 481.1911.

EXAMPLE 85-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

[0335]

[0336] Prepared using the amide from Preparation I and the methoddescribed for Example 6.

[0337]¹H NMR (400 MHz, CD₃OD): δ 7.32 (2H, d), 7.18 (1H, s), 6.98 (3H,m), 6.60 (1H, d), 4.61 (1H, m), 4.56 (2H, s), 3.42 (2H, d), 3.02-2.89(2H, m), 2.80-2.61 (4H, m), 2.15-2.07 (2H, m), 1.97-1.77 (4H, m), 1.11(3H, d).

[0338] LRMS (ESI): m/z [M+H]⁺452.

EXAMPLE 9 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopentylmethyl)-1H-indole-2-carboxamide

[0339]

[0340] Prepared using the amide from Preparation 2 and the methoddescribed for Example 6.

[0341]¹H NMR (400 MHz, CD₃OD): δ 7.33 (2H, d), 7.19 (1H, s), 6.99 (3H,m), 6.62 (1H, d), 4.67-4.59 (1H, m), 4.57 (2H, s), 3.33 (2H, undersolvent peak), 3.05 (1H, m), 2.95 (1H, m), 2.85-2.68 (3H, m), 2.28-2.20(1H, m), 1.85-1.77 (2H, m), 1.70-1.58 (4H, m), 1.37-1.28 (2H, m), 1.13(3H, d).

[0342] HRMS (ESI): m/z [M+H]⁺ found 466.2694; requires 466.2707.

EXAMPLE 105-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0343]

[0344] Prepared using the amide from Preparation 3 and the methoddescribed for Example 6.

[0345]¹H NMR (400 MHz, CD₃OD): δ 7.32 (2H, d), 7.12 (1H, s), 6.97 (3H,m), 6.60 (1H, d), 4.60 (1H, m), 4.56 (2H, s), 3.23 (2H, d), 3.07-2.89(2H, m), 2.79-2.63 (3H, m), 1.84-1.59 (6H, m), 1.34-1.18 (3H, m), 1.11(3H, d), 1.08-0.97 (2H, m).

[0346] HRMS (ESI): m/z [M+H]+found 480.2839; requires 480.2864.

EXAMPLE 115-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-methylsulfamoylbenzyl)-1H-indole-2-carboxamide

[0347]

[0348] Preparation 6 (100 mg, 201 μmol), WSCDI (42 mg, 221 μmol), HOBt(30 mg, 221 μmol), pyridine (17 mg, 221 μmol) and4-aminomethyl-N-methylbenzenesulfonamide (40 mg, 201 μmol) were stirredin DMF (5 ml) overnight. The solvent was removed and the product takenup in CH₂Cl₂ and washed with water. The solvent was removed and thecrude material taken up in MeOH (5.7 ml) and water (10 ml) and treatedwith ammonium fluoride (43 mg, 115 μmol) and stirred at 40° C.overnight. The solvent was removed and the crude material purified twiceby chromatography (10-20% MeOH in CH₂Cl₂+1% ammonia) (18 mg).

[0349]¹H NMR (400 MHz, CD₃OD): δ 7.79 (2H, d) 7.58 (3H, d), 7.43 (1H,d), 7.45 (1H, s), 7.15 (3H, t), 6.78 (1H, d), 4.62 (5H, d), 3.59 (1H,m), 3.19 (1H, m), 3.18 (2H, m), 2.85 (1H, t), 2.50 (3H, s), 1.25 (3H,d).

[0350] LRMS (ESI): m/z [M+H]⁺567.

EXAMPLE 125-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-sulfamoylbenzyl)-1H-indole-2-carboxamide

[0351]

[0352] Prepared using the acid from Preparation 6 and the methoddescribed for Example 11.

[0353]¹H NMR (400 MHz, CD₃OD): δ 7.82 (2H, d), 7.50 (3H, d), 7.42 (1H,d), 7.30 (1H, s), 7.12 (2H, d), 7.09 (1H, s), 6.78 (1H, d), 4.62 (5H,d), 3.60 (1H, m), 3.22 (1H, m), 3.18 (2H, m), 2.82 (1H, m), 1.22 (3H,d).

[0354] LRMS (ESI): m/z [M+H]⁺553.

EXAMPLE 131-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-methoxybenzyl)-1H-indole-2-carboxamide

[0355]

[0356] A solution of Preparation 31 (100 mg, 170 μmol), WSCDI (42 mg,219 μmol), HOBt (34 mg, 255 μmol) and pyridine (33 mg, 340 μmol) in DMF(2 ml) was treated with 2-methoxybenzylamine (23 mg, 170 μmol) and themixture stirred at RT under a nitrogen atmosphere for 18 hours. Thesolvent was removed and residue partitioned between CH₂Cl₂ (6 ml) andwater (6 ml). The organic phase was reduced in vacuo and the crudematerial was taken up in MeOH (8 ml) and treated with ammonium fluoride(72 mg, 1.95 mmol) in water (4 ml) and stirred at 40° C. overnight. Thesolvent was removed and the product purified by chromatography (2% MeOHin CH₂Cl₂+0.2% ammonia) (20 mg).

[0357]¹H NMR (400 MHz, CD₃OD): δ 7.33 (1H, s), 7.28-7.11 (7H, m),7.01-6.92 (6H, m), 6.83 (1H, t), 6.60 (1H, d), 5.77 (2H, s), 4.61-4.57(1H, m), 4.55 (2H, s), 5.42 (2H, s), 3.83 (3H, s), 2.98-2.88 (2H, m),2.76-2.65 (3H, m), 1.09 (3H, d).

[0358] LRMS (ESI): m/z [M+H]⁺594.

EXAMPLE 141-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide

[0359]

[0360] Prepared using the acid from Preparation 31 and the methoddescribed for Example 13.

[0361]¹H NMR (400 MHz, CD₃OD): δ 7.39-6.99 (16H, m), 6.65 (1H, d), 5.75(2H, s), 5.21 (1H, q), 4.66-4.60 (3H, m), 2.93-3.02 (2H, m), 2.80-2.70(3H, m), 1.57 (3H, d), 1.14 (3H, d).

[0362] LRMS (ESI): m/z [M+H]⁺578.

EXAMPLE 151-Ethyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-2-Phenylethyl)-1H-indole-2-carboxamide

[0363]

[0364] Prepared using the acid from Preparation 26 and the methoddescribed for Example 13.

[0365]¹H NMR (400 MHz, CD₃OD): δ 7.45 (2H, m), 7.39-7.32 (4H, m), 7.26(1H, m), 7.21 (1H, bs), 7.06-6.98 (3H, m), 6.64 (1H, d), 5.26 (1H, q),4.63 (1H, m), 4.57 (2H, m), 4.52 (2H, q), 3.01-2.93 (2H, m), 2.75-2.68(3H, m), 1.61 (3H, d), 1.32 (3H, t), 1.14 (3H, d).

[0366] LRMS (ESI): m/z [M+H]⁺516.

EXAMPLE 165-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl)-1-methyl-1H-indole-2-carboxamide

[0367]

[0368] Prepared using the acid from Preparation 21 and the methoddescribed for Example 13.

[0369]¹H NMR (400 MHz, CD₃OD): δ 7.43 (2H, d), 7.33 (2H, t), 7.27-7.23(3H, m), 7.13 (1H, bs), 7.00-6.89 (3H, m), 6.54 (1H, d), 5.23 (1H, q),4.574.54 (1H, m), 4.54-4.46 (2H, m), 3.91 (3H, m), 2.95-2.87 (2H, m),2.74-2.59 (3H, m), 1.58 (3H, d), 1.10 (3H, d).

[0370] LRMS (ESI): m/z [M+H]⁺502.

EXAMPLE 171-Benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2.6-dimethoxybenzyl)-1H-indole-2-carboxamide

[0371]

[0372] Prepared using the acid from Preparation 31 and the methoddescribed for Example 13.

[0373]¹H NMR (400 MHz, CD₃OD): δ 7.33-7.89 (12H, m), 6.70 (2H, s), 6.62(1H, d), 5.81 (2H, s), 4.66-4.58 (5H, m), 3.86 (6H, s), 2.99-2.90 (2H,m), 2.76-2.67 (3H, m), 1.13(3H, d).

[0374] LRMS (ESI): m/z [M+H]⁺624.

EXAMPLE 18 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)butyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide

[0375]

[0376] A solution of Preparation 39 (153 mg, 220 μmol) in ethanol (10ml) was treated with ammonium formate (70 mg, 1.1 mmol) and palladiumhydroxide on carbon (20%, 10 mg) and heated to reflux for 2 h. Ammoniumfluoride (40 mg, 1.1 mmol) in water (1 ml) was then added and theresulting mixture stirred at 40° C. for 24 h. The solvents were thenremoved and the crude material taken up in ethyl acetate, washed withwater (containing 1% 0.88 ammonia) and dried (Na₂SO₄). The product waspurified by chromatography (2-5% MeOH in CH₂Cl₂ and 0.3% NH₃) to yield ayellow semi-solid. This was taken up in THF (3 ml) and water (0.5 ml)and treated with LiOH (1N, 100 μl) and stood at RT overnight. Thesolvents were removed and the product purified by chromatography (5%MeOH in CH₂Cl₂+0.3% MeOH) (60 mg).

[0377]¹H NMR (400 MHz, CD₃OD): δ 7.43-7.41 (2H, m), 7.34-7.27 (4H, m),7.22 (1H, t), 7.15 (1H, m), 7.09 (1H, s), 7.00-6.90 (2H, d), 6.57 (1H,d), 5.26 (1H, q), 4.55 (3H, m, s), 2.87-2.60 (5H, m), 1.58 (3H, d), 1.55(1H, m), 1.44 (1H, m), 0.96 (3H, t).

[0378] LRMS (ESI): m/z [M+H]⁺502.

EXAMPLE 19 5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)butyl}-N-[3-methyl-pyridin-2-ylmethyl]-1H-indole-2-carboxamide

[0379]

[0380] Prepared using the acid from Preparation 41 and the methoddescribed for Preparation 6.

[0381]¹H NMR (400 MHz, CD₃OD): δ 8.40 (1H, d), 7.65 (1H, d), 6.90-7.35(7H, m), 6.60 (1H, d), 4.70 (2H, s), 4.60 (1H, m), 4.50 (2H, s),2.60-3.00 (5H, m), 2.40 (3H, s), 1.05 (3H, d).

[0382] HRMS: C₂₈H₃₂N₄O₄Si requires: 489.2503 found 489.2492 [M+H]⁺.

[0383] The following Preparations describe the preparation of certainintermediates used in the preceding Examples.

[0384] Preparation 1:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-[cyclobutylmethyl]-1H-indole-2-carboxamide

[0385] A solution of Preparation 6 (150 mg, 300 μmol), WSCDI (63 mg, 330μmol), HOBt (45 mg, 330 μmol) and pyridine (54 mg, 661 μmol) in DMF (2ml) was treated with Preparation 40 (40 mg, 330 μmol) and the mixturestirred at RT under a nitrogen atmosphere for 18 hours. The solvent wasremoved and the crude material taken up in CH₂Cl₂:MeOH (9:1) (10 ml) andwashed with sat. ammonium chloride solution (2×5 ml). The precipitatewas redissolved in CH₂Cl₂:MeOH (9:1) (10 ml) and the combined organicsdried (Na₂SO₄). After removal of the solvent the material was trituratedwith EtOH and Et₂O and the solid filtered off. The filtrate left a lightbrown coloured foam (144 mg).

[0386]¹H NMR (400 MHz, CD₃OD): δ 7.50 (2H, m), 7.32 (1H, s), 7.10 (3H,m), 6.80 (1H, d), 5.03 (1H, m), 4.65 (2H, dd), 3.40 (2H, m), 3.05-3.12(3H, m), 2.95 (1H, m), 2.65 (2H, m), 2.10 (2H, m), 1.90 (2H, m), 1.80(2H, m), 1.33 (3H, d), 0.78 (9H, s), 0.00 (3H, s), −0.20 (3H, s).

[0387] LRMS (electrospray): m/z [M+H]⁺566.

[0388] Preparation 2:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(cyclopentylmethyl)-1H-indole-2-carboxamide

[0389] Prepared using the acid from Preparation 6 and the methoddescribed for Preparation 1.

[0390]¹H NMR (400 MHz, CD₃OD): δ 7.48 (2H, m), 7.30 (1H, s), 7.10 (3H,m), 6.78 (1H, d), 5.01 (1H, m), 4.70-4.61 (2H, m), 3.60 (1H, m), 3.36(2H, under solvent peak), 3.18-3.08 (3H, m), 2.94 (1H, m), 2.24 (1H, m),1.84-1.76 (2H, m), 1.68-1.58 (4H, m), 1.36-1.29 (5H, m), 0.76 (9H, s),0.00 (3H, s), −0.19 (3H, s).

[0391] LRMS (electrospray): m/z [M+H]⁺580.

[0392] Preparation 3:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(cyclohexylmethyl)-1H-indole-2-carboxamide

[0393] Prepared using the acid from Preparation 6 and the methoddescribed for Preparation 1.

[0394]¹H NMR (400 MHz, CD₃OD): δ 7.42 (2H, m), 7.24 (1H, s), 7.04 (3H,m), 6.71 (1H, d), 4.88 (1H, under solvent peak), 4.63 (2H, m), 3.35 (1H,under solvent peak), 3.23 (2H, d), 3.15 (1H, m), 2.96-2.82 (3H, m),1.83-1.60 (6H, m), 1.33-1.17 (3H, m), 1.22 (3H, d), 0.98 (2H, q), 0.74(9H, s), −0.05 (3H, s), −0.23 (3H, s).

[0395] LRMS (electrospray): m/z [M+H]⁺594.

[0396] Preparation 4:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(thiazol-2-ylmethyl)-1H-indole-2-carboxamide

[0397] Prepared using the acid from Preparation 6 and the methoddescribed for Preparation 1.

[0398]¹H NMR (400 MHz, CD₃OD): δ 7.71 (1H, d), 7.50 (1H, d), 7.34 (2H,m), 7.16 (1H, s), 7.06 (1H, s), 7.01 (1H, d), 6.93 (1H, d), 6.61 (1H,d), 4.89 (2H, s), 4.68 (1H, m), 4.54-4.62 (2H, m), 2.99 (1H, m), 2.90(1H, m), 2.71 (2H, d), 2.64 (1H, m), 1.09 (3H, d), 0.71 (9H, s), −0.09(3H, s), −0.26 (3H, s).

[0399] LRMS (APCI): m/z [M+H]⁺595.

[0400] Preparation 5:5-[(2R)-2-([(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-[(1R)-1phenylethylamine)-1H-indole-2-carboxamide

[0401] Prepared using the acid from Preparation 6 and the methoddescribed for Preparation 1.

[0402]¹H NMR (400 MHz, CD₃OD): crude material

[0403] LRMS (APCI): m/z [M]⁺602.

[0404] Preparation 6:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylic acid

[0405] A solution of Preparation 7 (0.30 g, 0.59 mmol) in 1,4-dioxane(10 ml) was treated with a solution of sodium hydroxide (59 mg, 1.46mmol) in water (1 ml) and the resulting mixture left to stir at roomtemperature for 30 minutes. After this time the reaction mixture washeated to 90° C. for 30 minutes and then cooled to room temperature. Thesolvent was removed in vacuo and the residue re-dissolved in water (20ml) and pH adjusted to 7 by addition of 2N hydrochloric acid. The solidthat formed was filtered off, solubilised in a mixture ofdichloromethane and methanol (20 ml 90:10 by volume), dried (magnesiumsulphate) and the solvent removed in vacuo to give the title compound asa pale orange foam.

[0406]¹H NMR (400 MHz, CD₃OD): δ=7.47-7.42 (2H, m), 7.27 (1H, s),7.11-7.03 (3H, m), 6.76-6.74 (1H, d), 4.99-4.97 (1H, m), 4.67-4.58 (2H,m); 3.60-3.55 (1H, m), 3.28-3.26 (1H, m), 3.16-3.12 (1H, m), 3.09-3.04(1H, m), 2.94-2.88 (1H, m), 1.28-1.26 (3H, d), 0.74 (9H, s), −0.03 (3H,s), −0.22 (3H, s).

[0407] LRMS (electrospray): m/z [M+H]⁺, 499.

[0408] Preparation 7: Methyl5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate

[0409] A suspension of Preparation 8 (0.38 g, 0.63 mmol) and 10%palladium on carbon (78 mg) in ethanol (20 ml) was stirred under anatmosphere of hydrogen (60 psi) at room temperature for 16 hours. Thecatalyst was filtered off through arbocel and the solvent removed invacuo to give the title compound as a pale pink foam (316 mg), which wasused without further purification.

[0410]¹H NMR (400 MHz, CD₃OD): δ=7.36-7.32 (2H, m), 7.15 (1H, bs), 7.09(1H, bs), 7.05-7.04 (1H, m), 6.95-6.93 (1H, m), 6.62 (1H, d), 4.69-4.66(1H, m), 4.57 (2H, s), 3.92 (3H, s), 2.98-2.85 (2H, m), 2.70 (2H, d),2.63-2.59 (1H, m), 1.08 (3H, d), 0.71 (9H, s), −0.09 (3H, s), −0.26 (3H,s).

[0411] LRMS (electrospray): m/z [M+H]+513, [M+Na]⁺535.

[0412] Analysis: Found C 64.89; H 7.93; N 5.08; C₂₈H₄₀N₂O₅Si. 0.25H₂Orequires C 65.02; H 7.89; N 5.42

[0413] Optical Rotation [α]_(D) ²⁵=−84.02° 0.4 mg/ml MeOH 635 nm

[0414] Preparation 8: Methyl5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-1H-indole-2-carboxylate

[0415] Preparation 9 (4.55 g, 19.6 mmol), Preparation 15 (8.55 g, 19.6mmol) and diisopropylethylamine (2.53 g, 19.6 mmol) were stirred andheated to 100° C. overnight. Ethyl acetate (300 ml) was added and theorganic washed with water (2×500 ml). The aqueous phases were washedwith ethyl acetate (200 ml) and the combined organics washed with brine(500 ml) and dried (Na₂SO₄). The crude material was purified bychromatography (0-3% MeOH in CH₂Cl₂ with 0.5% NH₃) the title compound asa pale yellow oil (5.72 g).

[0416]¹H NMR (400 MHz, CD₃OD): δ=7.44-7.27 (8H, m), 7.08-7.04 (2H, m),6.96-6.93 (1H, m), 6.67 (1H, d), 4.98 (2H, s), 4.724.67 (1H, m), 4.60(2H, s), 3.82 (3H, s), 2.99-2.89 (2H, m), 2.77-2.72 (1H, m), 2.65-2.59(2H, m), 1.11 (3H, d), 0.74 (9H, s), −0.07 (3H, s), −0.24 (3H, s).

[0417] LRMS (electrospray): m/z [M+H]+603, [M+Na]⁺625.

[0418] Analysis: Found C 69.26; H 7.72; N 4.61; C₃₅H₄₆N₂O₅Si. 0.2H₂Orequires C 69.32; H 7.71; N 4.62

[0419] Preparation 9: Methyl5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate

[0420] A solution of Preparation 10 (9.34 g, 25.0 mmol) in ethanol (125ml) was treated with ammonium formate (7.90 g, 125 mmol) and palladiumhydroxide on carbon (2.81 g, 20% b/w palladium). The resultingsuspension was purged with nitrogen and then heated to reflux for anhour. The reaction mixture was cooled to room temperature and filteredthrough arbocel to remove catalyst residues. The filtrate was reduced invacuo and the residue was partitioned between 0.88 ammonia (100 ml) anddichloromethane (100 ml). The organic phase was separated and theaqueous extracted with more dichloromethane (100 ml). The combinedorganic extracts were dried (sodium sulphate) and the solvent removed invacuo to give the title compound as a colourless oil (6.25 g, tracesolvent remaining by ¹H NMR).

[0421]¹H NMR (400 MHz, CD₃OD): δ=7.44 (1H, bs), 7.36 (1H, d), 7.13 (1H,d), 7.11 (1H, s), 3.90 (3H, s), 3.17-3.07 (1H, m), 2.77-2.61 (2H, m),1.10 (3H, d).

[0422] LRMS (electrospray): m/z [M+H]+233, [M+Na]+255.

[0423] Optical Rotation [α]_(D) ²⁵=−22.58° 6.76 mg/ml MeOH 589 nm

[0424] Preparation 10: Methyl5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2-carboxylatehydrochloride

[0425] A solution of Preparation 11 (20.48 g, 46.9 mmol) was treatedwith 4M hydrogen chloride in methanol and the resulting solution left tostir at room temperature for 16 hours and then heated at 50° C. for afurther 2 hours. The solvent was removed in vacuo to give a solid whichwas crystallised from a mixture of methanol (125 ml) anddiisopropylether (50 ml) to give the title compound as a colourlesscrystalline solid (9.34 g, d.e.>98% as determined by ¹H NMR).

[0426]¹H NMR (400 MHz, CD₃OD): δ=7.53-7.49 (5H, m), 7.40-7.38 (2H, m),7.10, 1H, bs), 6.97 (1H, bd), 4.61 (1H, q), 3.91 (3H, s), 3.42-3.37 (1H,m), 3.26-3.19 (1H, m), 2.72-2.66 (1H, m), 1.69 (3H, d), 1.19 (3H, d).

[0427] LRMS (electrospray): m/z [M+H]⁺337.

[0428] Preparation 11: 1-tert-butyl 2-methyl5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-1.2-dicarboxylate

[0429] A solution of Preparation 12 (18.0 g, 54.32 mmol),(R)-α-methylbenzylamine (6.4 ml, 49.65 mmol), sodiumtriacetoxyborohydride (15.80 g, 74.55 mmol) and acetic acid (3.0 ml,52.38 mmol) in dichloromethane (500 ml) was stirred at room temperaturefor 16 hours. The reaction mixture was quenched by addition of saturatedaqueous sodium bicarbonate (200 ml) and allowed to stir untileffervescence ceased. The organic phase was separated and the aqueousphase extracted with further dichloromethane (100 ml). The combinedorganic extracts were dried (magnesium sulphate) and the solvent removedin vacuo. The residue was purified by flash column chromatography onsilica gel eluting with dichloromethane:methanol:0.88 ammonia (99:1:0.1changing to 98:2:0.2, by volume) to give a 4:1 mixture of diastereomers(R,R major) as a pale yellow oil (20.48 g).

[0430]¹H NMR (400 MHz, CD₃OD): δ=7.97-7.92 (1H, m), 7.41-7.02 (8H, m),4.04-3.99 (1H, m), 3.96-3.94 (3H, m), 3.15-3.10 (1H, m), 2.80-2.70 (1H,m), 2.53-2.48 (1H, m), 1.66 (9H, s), 1.39-1.31 (3H, 2d), 1.10-0.95 (3H,2d).

[0431] LRMS (electrospray): m/z [M+H]⁺437.

[0432] Preparation 12: 1-tert-butyl 2-methyl5-(2-oxopropyl)-1H-indole-1,2-dicarboxylate

[0433] A solution of Preparation 13 (12.5 g, max 32.04 mmol),tributyltin methoxide (11.0 ml, 38.2 mmol), isoprenylacetate (5.3 ml,48.1 mmol), palladium acetate (0.36 g, 5 mol %), tri-o-tolylphosphine(0.97 g, 10 mol %) in toluene (40 ml) was degassed and then heated at100° C. for 8 hours. The reaction mixture was diluted with ethyl acetate(50 ml), 4M potassium fluoride (aqueous, 100 ml) and left to stir atroom temperature overnight. The resulting mixture was filtered througharbocel washing the precipitate thoroughly with ethyl acetate (100 ml)and the organic phase of the filtrate separated, dried (magnesiumsulphate) and the solvent removed in vacuo. The residue was purified byflash column chromatography on silica gel eluting with pentane:ethylacetate (95:5 changing to 90:10, by volume) to give the title compound(8.2 g) as a yellow oil.

[0434]¹H NMR (400 MHz, CDCl₃): δ=8.05 (1H, d), 7.44 (1H, s), 7.25 (1H,d), 7.05 (1H, s), 3.92 (3H, s), 3.78 (2H, s), 2.16 (3H, s), 1.61 (9H,s).

[0435] LRMS (electrospray): m/z [M−H]⁻330, [M+Na]⁺354.

[0436] Preparation 13: 1-tert-Butyl 2-methyl5-bromo-1H-indole-1.2-dicarboxylate

[0437] A solution of Preparation 14 (8.14 g, 32.04 mmol) intetrahydrofuran (300 ml) was added to sodium hydride (1.35 g of a 40%dispersion in mineral oil, 33.7 mmol) at 0° C. under nitrogen. Theresulting mixture was left to stir until effervescence ceased (50minutes). A solution of di-tert-butyldicarbonate in furthertetrahydrofuran (30 ml) was added to the reaction and the resultingmixture stirred vigorously, warming gradually to room temperatureovernight. The solvent was removed in vacuo and the residue partitionedbetween ethyl acetate (200 ml) and water (200 ml). The organic phase wasseparated and the aqueous extracted with more ethyl acetate (2-fold 200ml). The combined organics were dried (magnesium sulphate) and thesolvent removed in vacuo to give the title compound as a pale yellow oil(12.5 g—trace solvent remaining).

[0438]¹H NMR (400 MHz, CDCl₃): δ=7.98 (1H, d), 7.74 (1H, s), 7.50 (1H,dd), 7.00 (1H, s), 3.92 (3H, s), 1.61 (9H, s).

[0439] LRMS (electrospray): m/z [M+H]⁺352/354, [M+Na]⁺376/378.

[0440] Preparation 14: Methyl 5-bromo-1H-indole-2-carboxylate

[0441] A solution of 5-Bromo-1H-indole-2-carboxylic acid (commercial,10.0 g, 41.6 mmol) in methanol (200 ml) was cooled to 0° C. andsaturated with HCl (g). The resulting solution was allowed to warmgradually to room temperature overnight. The solvent was removed invacuo and the residue treated with 0.88 ammonia (500 ml). The resultingsolution was extracted with dichloromethane (3-fold 150 ml) and thecombined organics dried (magnesium sulphate) and the solvent removed invacuo to give the required product as a colourless oil (8.35 g).

[0442]¹H NMR (400 MHz, CDCl₃): δ=8.96 (1H, bs), 7.83 (1H, s), 7.40 (1H,d), 7.30 (1H, d), 7.14 (1H, s), 3.95 (3H, s).

[0443] LRMS (electrospray): m/z [M−H]-252/254.

[0444] Preparation 15:[2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol

[0445] Borane methylsulfide complex (42.4 ml of ˜10M solution, 424 mmol)was added drop wise to a solution of Preparation 16 (91.0 g) intetrahydrofuran (1600 ml). The resulting mixture was then heated toreflux for 2 hours and then cooled to 0° C. before quenching withmethanol (270 ml). The mixture was left to stir at room temperature for16 hours and then the solvent removed in vacuo. The residue waspartitioned between dichloromethane (500 ml) and water (500 ml). Theaqueous phase was separated and extracted with more dichloromethane (500ml) and the combined organic extracts washed with saturated aqueoussodium chloride (500 ml), dried (magnesium sulphate) and the solventremoved in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with cyclohexane:ethyl acetate(100:0 changing to 80:20, by volume) to give the title compound (68.7 g)as a colourless oil.

[0446]¹H NMR (400 MHz, CDCl₃): δ=7.42-7.36 (5H, m), 7.29-7.25 (3H, m),6.94 (1H, d), 5.12 (2H, s), 4.84-4.81 (1H, m), 4.74 (2H, s), 3.48-3.40(2H, m), 0.90 (9H, s), 0.11 (3H, s), −0.07 (3H, s).

[0447] LRMS (electrospray): m/z [M+Na]⁺473/475.

[0448] Preparation 16: Methyl2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate

[0449] A solution of methyl2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.05 g, 195mmol), imidazole (18.52 g, 272 mmol), tert-butyldimethylsilyl chloride(32.23 g, 214 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.6 mmol) inDMF (270 ml) was left to stir at room temperature under a nitrogenatmosphere for a period of 24 hours. The solvent was removed in vacuoand the residue partitioned between ethyl acetate (500 ml) and water(500 ml). The organic phase was separated and washed with 2Nhydrochloric acid (2-fold 500 ml), saturated aqueous sodium bicarbonate(2×500 ml) saturated sodium chloride (500 ml), dried (magnesiumsulphate) and the solvent removed in vacuo to give the title compound asa colourless oil (91.0 g).

[0450]¹H NMR (400 MHz, CDCl₃): δ=7.81 (1H, bs), 7.51-7.30 (6H, m), 7.01(1H, d), 5.19 (2H, s), 4.85-4.82 (1H, m), 3.91 (3H, s), 3.48-3.39 (2H,m), 0.90 (9H, s), 0.11 (3H, s), −0.08 (3H, s).

[0451] LRMS (electrospray): m/z [M+Na]⁺501/503.

[0452] Preparation 17: Ethyl1-methyl-5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2-carboxylatehydrochloride

[0453] Prepared using the procedure of Preparation 11 giving the titlecompound as a a 4:1 mixture of diastereomers (R,R major). The crudematerial was treated with excess HCl in MeOH and then crystallised fromDIPE/MeOH to give the R,R isomer (d.e.>98% as determined by ¹H NMR).

[0454]¹H NMR (400 MHz, CD₃OD) δ 7.56-7.48 (5H, m), 7.43-7.40 (2H, m),7.19 (1H, s), 7.04 (1H, d), 4.62 (1H, q), 4.35 (2H, q), 4.03 (3H, s),3.45-3.40 (1H, m), 3.28-3.21 (1H, m), 2.74-2.69 (1H, m), 1.70 (3H, d),1.39 (3H, t), 1.19 (3H, d).

[0455] LRMS (ESI): m/z [M+H]+635, [M+Na]+387.

[0456] Preparation 18: Ethyl1-methyl-5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate

[0457] Prepared using the amine from Preparation 17 and the methoddescribed for Preparation 9.

[0458]¹H NMR (400 MHz, CD₃OD): δ 7.46-7.40 (2H, m), 7.22-7.19 (2H, m),4.35 (2H, q), 4.04 (3H, s), 3.18-3.10 (1H, m), 2.77-2.65 (2H, m), 1.39(3H, t), 1.10 (3H, d).

[0459] LRMS (ESI): m/z [M+H]+261, [M+Na]⁺283.

[0460] Preparation 19: Ethyl1-methyl-5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-1H-indole-2-carboxylate

[0461] Prepared using the amine from Preparation 18, and the bromidefrom Preparation 15 and the method described for Preparation 8.

[0462]¹H NMR (400 MHz, CD₃OD): δ 7.43-7.26 (8H, m), 7.18 (1H, bs), 7.10(1H, d), 6.98 (1H, d), 6.72 (1H, d), 4.99 (2H, s), 4.71-4.68 (1H, m),4.58 (2H, s), 4.29 (2H, q), 4.01 (3H, s), 2.98-2.90 (2H, m), 2.78-2.73(1H, m), 2.65-2.58 (2H, m), 1.36 (3H, t), 1.11 (3H, d), 0.73 (9H, s),−0.07 (3H, s), −0.24 (3H, s).

[0463] LRMS (ESI): m/z [M+H]⁺631, [M+Na]⁺653.

[0464] Preparation 20: Ethyl1-methyl-5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate

[0465] Prepared using the ester from Preparation 19 and the methoddescribed for Preparation 7.

[0466]¹H NMR (400 MHz, CD₃OD): δ 7.35-7.31 (2H, m), 7.18 (1H, s),7.11-7.06 (2H, m), 6.92 (1H, d), 6.58 (1H, d), 4.66-4.63 (1H, m), 4.53(2H, s), 4.37 (2H, q), 4.05 (3H, s), 2.96-2.87 (2H, m), 2.76-2.56 (3H,m), 1.40 (3H, t), 1.10 (3H, d), 0.72 (9H, s), −0.08 (3H, s), −0.26 (3H,s).

[0467] LRMS (ESI): m/z [M+H]⁺541, [M+Na]⁺563.

[0468] Preparation 21:1-Methyl-5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylicacid

[0469] Prepared using the ester from Preparation 20 and the methoddescribed for Preparation 6.

[0470]¹H NMR (400 MHz, CD₃OD): δ 7.44-7.39 (2H, m), 7.25 (1H, s),7.16-7.00 (3H, m), 6.72 (1H, d), 4.99-4.96 (1H, m), 4.64-4.56 (2H, m),4.02 (3H, s), 3.60-3.54 (1H, m), 3.13-2.89 (4H, m), 1.27-1.26 (3H, m),0.72 (9H, s), −0.04 (3H, s), −0.24 (3H, s).

[0471] LRMS (ESI): m/z [M+H]⁺513, [M+Na]⁺535.

[0472] Preparation 22: Ethyl1-ethyl-5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2-carboxylatehydrochloride

[0473] Prepared using the method described for Preparation 11 giving thetitle compound as a a 4:1 mixture of diastereomers (R,R major). Thecrude material was treated with excess HCl in MeOH and then crystallisedfrom DIPE/MeOH to give the R,R isomer (d.e.>98% as determined by ¹HNMR).

[0474]¹H NMR (400 MHz, CD₃OD): δ 7.57-7.45 (7H, m), 7.24 (1H, s), 7.07(1H, d), 4.68-4.63 (3H, m), 4.40 (2H, q), 3.52-3.44 (1H, m), 3.29-3.25(1H, m), 2.78-2.72 (1H, m), 1.74 (3H, d), 1.44 (3H, t), 1.37 (3H, t),1.24 (3H, d).

[0475] LRMS (ESI): m/z [M+H]⁺379, [M+Na]⁺401.

[0476] Preparation 23: Ethyl1-ethyl-5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate

[0477] Prepared using the amine from Preparation 22 and the methoddescribed for Preparation 9.

[0478]¹H NMR (400 MHz, CD₃OD): δ=7.46-7.41 (2H, m), 7.20-7.18 (2H, m),4.61 (2H, q), 4.35 (2H, q), 3.17-3.09 (1H, m), 2.77-2.64 (2H, m), 1.39(3H, t), 1.34 (3H, t), 1.10 (3H, d).

[0479] LRMS (ESI): m/z [M+H]⁺275, [M+Na]⁺297.

[0480] Preparation 24: Ethyl1-ethyl-5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-1H-indole-2-carboxylate

[0481] Prepared using the amine from Preparation 23, and the bromidefrom preparation 15 and the method described for Preparation 8.

[0482]¹H NMR (400 MHz, CD₃OD): δ=7.43-7.29 (8H, m), 7.19 (1H, s), 7.11(1H, d), 6.99 (1H, d), 6.74 (1H, d), 5.00 (2H, s), 4.73-4.70 (1H, m),4.61-4.56 (4H, m), 4.30 (2H, q), 3.00-2.88 (2H, m), 2.78-2.61 (3H, m),1.37-1.31 (6H, m), 1.11 (3H, d), 0.73 (9H, s), −0.08 (3H, s), −0.24 (3H,s).

[0483] LRMS (ESI): m/z [M+H]⁺645, [M+Na]⁺667.

[0484] Preparation 25: Ethyl1-ethyl-5-[(2R)-2-({(2R)-2-{]tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate

[0485] Prepared using the amine from Preparation 24 and the methoddescribed for Preparation 7.

[0486]¹H NMR (400 MHz, CD₃OD): δ 7.38-7.35 (2H, m), 7.19-7.09 (3H, m),6.96 (1H, d), 6.64 (1H, d), 4.68-4.58 (5H, m), 4.37 (2H, q), 2.98-2.60(5H, m), 1.41 (3H, t), 1.36 (3H, t), 1.10 (3H, d), 0.72 (9H, s), −0.09(3H, s), −0.25 (3H, s).

[0487] LRMS (ESI): m/z [M+H]⁺555, [M+Na]⁺577.

[0488] Preparation 26:1-Ethyl-5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylicacid

[0489] Prepared using the amine from Preparation 25 and the methoddescribed for Preparation 6.

[0490]¹H NMR (400 MHz, CD₃OD): δ 7.41-7.35 (2H, m), 7.21 (1H, bs),7.07-6.95 (3H, m), 6.67 (1H, d), 4.94-4.91 (1H, m), 4.60-4.55 (4H, m),3.54-3.49 (1H, m), 3.09-2.84 (4H, m), 1.27-1.21 (6H, m), 0.67 (9H, s),−0.09 (3H, s), −0.29 (3H, s).

[0491] LRMS (ESI): m/z [M+H]⁺527, [M+Na]⁺549.

[0492] Preparation 27: Ethyl1-benzyl-5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2-carboxylatehydrochloride

[0493] Prepared using the method described for Preparation 11 giving thetitle compound as a a 4:1 mixture of diastereomers (R,R major). Thecrude material was treated with excess HCl in MeOH and then crystallisedfrom DIPE/MeOH to give the R,R isomer (d.e.>98% as determined by ¹HNMR).

[0494]¹H NMR (400 MHz, CD₃OD): δ 7.51-7.45 (6H, m), 7.37 (1H, d), 7.30(1H, s), 7.22-7.16 (3H, m), 7.01-6.97 (3H, m), 5.84 (2H, s), 4.59 (1H,q), 4.31 (2H, q), 3.42-3.38 (1H, m), 3.28-3.19 (1H, m), 2.75-2.70 (1H,m), 1.69 (3H, d), 1.33 (3H, t), 1.20 (3H, d).

[0495] LRMS (ESI): m/z [M+H]⁺441.

[0496] Preparation 28: Ethyl1-benzyl-5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate

[0497] Prepared using the amine from Preparation 27 and the methoddescribed for Preparation 9.

[0498]¹H NMR (400 MHz, CD₃OD): δ 7.55 (1H, s), 7.41 (1H, d), 7.36 (1H,s), 7.28-7.20 (4H, m), 7.05 (2H, d), 5.89 (2H, s), 4.35 (2H, q),3.20-3.14 (1H, m), 2.82-2.69 (2H, m), 1.38 (3H, t), 1.15 (3H, d)

[0499] LRMS (ESI): m/z [M+H]+337.

[0500] Preparation 29: Ethyl1-benzyl-5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}-1H-indole-2-carboxylate

[0501] Prepared using the amine from Preparation 26, and the bromidefrom preparation 15 and the method described for Preparation 8.

[0502]¹H NMR (400 MHz, CD₃OD): δ 7.47-7.34 (10H, m), 7.27-7.19 (3H, m),7.13-7.00 (3H, m), 6.75 (1H, d), 5.86 (2H, s), 5.02 (2H, s), 4.78-4.75(1H, m), 4.71-4.69 (2H, m), 4.33-4.24 (2H, m), 3.05-2.91 (2H, m),2.83-2.78 (1H, m), 2.71-2.66 (2H, m), 1.33 (3H, t), 1.16 (3H, d), 0.79(9H, s), −0.03 (3H, s), −0.19 (3H, s).

[0503] LRMS (ESI): m/z [M+H]⁺707.

[0504] Preparation 30: Ethyl1-benzyl-5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylate

[0505] Prepared using the ester from Preparation 29 and the methoddescribed for Preparation 7.

[0506]¹H NMR (400 MHz, CD₃OD): δ 7.41 (1H, bs), 7.29-6.95 (10H, m), 6.65(1H, d), 5.82 (2H, s), 4.69-4.66 (1H, m), 4.62-4.55 (2H, m), 4.31 (2H,q), 2.98-2.85 (2H, m), 2.71-2.60 (3H, m), 1.34 (3H, t), 1.08 (3H, d),0.72 (9H, s), −0.10 (3H, s), −0.25 (3H, s).

[0507] LRMS (ESI): m/z [M+H]⁺617.

[0508] Preparation 31:1-Benzyl-5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-1H-indole-2-carboxylicacid

[0509] Prepared using the ester from Preparation 30 and the methoddescribed for Preparation 6.

[0510]¹H NMR (400 MHz, CD₃OD): δ=7.56 (1H, bs), 7.43-703 (10H, m), 6.80(1H, m), 5.95 (2H, s), 5.07-5.04 (1H, m), 4.73-4.64 (2H, m), 3.68-3.61(1H, m), 3.23-2.95 (4H, m), 1.33 (3H, d), 0.81 (9H, s), 0.04 (3H, s),−0.15 (3H, s).

[0511] LRMS (ESI): m/z [M+H]⁺589.

[0512] Preparation 32: Acetic acid 1-methylene-propyl ester

[0513] But-1-yne (13.5 g, 0.25 mol) was added to a solution of mercuricacetate (1.2 g, 4.6 mmol) and boron trifluoride dietherate (1.68 g, 11.8mmol) in acetic anhydride (40 ml) at −10° C. After stirring for 3 h, thesolution was left at −20° C. overnight. The reaction mixture was addedto a cooled (0° C.) 6.6 M solution of sodium hydroxide (150 ml). Diethylether (150 ml) was then added and the mixture stirred for 1 h. Theetheral layer was separated and washed with brine and dried (Na₂SO₄).The product was purified by distillation (120° C.) to yield a clear oil(4.5 g).

[0514]¹H NMR (400 MHz, CD₃OD): δ 4.75 (2H, 2×s), 2.20 (2H, q), 2.18 (3H,s), 1.05 (3H, t).

[0515] Preparation 33: 1-tert-Butyl 2-methyl5-(2-oxobutyl)-1H-indole-1,2-dicarboxylate

[0516] Prepared using the bromide from Preparation 13, the ester frompreparation 32 and the method described for Preparation 12.

[0517]¹H NMR (400 MHz, CDCl₃): δ 8.03 (1H, d), 7.44 (1H, s), 7.25 (1H, dpartially obscured by solvent), 7.05 (1H, s), 3.92 (3H, s), 3.77 (2H,s), 2.48 (2H, q), 1.62 (9H, s), 1.03 (3H, t).

[0518] LRMS (ESI): m/z [M+Na]⁺368.

[0519] Preparation 34: Methyl5-((2R)-2-{[(1R)-1-phenylethyl]amino}butyl)-1H-indole-2-carboxylate

[0520] Prepared using the ketone from Preparation 33 and the methoddescribed for Preparation 11.

[0521]¹H NMR (400 MHz, CD₃OD): δ 7.90 (1H, m), 7.29-7.23 (4h, m),7.20-6.82 (4H, m), 3.92 (3H, 2×s), 3.90 (1H, m), 2.89-2.53 (3H,m), 1.62(9H, s), 1.27 (3h, 2×d), 0.95-0.81 (3H, 2xt).

[0522] LRMS (APCI): m/z [M+H]⁺451.

[0523] Preparation 35: Methyl5-((2R)-2-{[(1R)-1-phenylethyl]amino}butyl)-1H-indole-2-carboxylatehydrochloride

[0524] Prepared using the amine from Preparation 34 and the methoddescribed for Preparation 10.

[0525]¹H NMR (400 MHz, CD₃OD): δ=7.50-7.41 (7H, m), 7.12 (1H, s), 7.03(1H, d), 4.43 (1H, q), 3.91 (3H, s), 3.31-3.24 (2H, m), 3.15-3.08 (1H,m), 2.98-2.92 (1H, m), 1.67 (3H, d), 1.66-1.51 (1H, m), 0.9 (3H, t).

[0526] LRMS (ESI): m/z [M+H]⁺351.

[0527] Preparation 36: Methyl5-[(2R)-2-aminobutyl]-1H-indole-2-carboxylate

[0528] Prepared using the amine from Preparation 35 and the methoddescribed for Preparation 9.

[0529]¹H NMR (400 MHz, CDCl₃) δ 9.39 (1H, bs), 7.49 (1H, s), 7.34 (1H,d), 7.13-7.15 (2H, m), 3.93 (3H, s), 2.99-2.88 (2H, m), 2.55-2.50 (1H,m), 1.51-1.20 (4H, m), 0.99 (3H, t).

[0530] LRMS (ESI): m/z [M+H]⁺247.

[0531] Preparation 37: Methyl5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]butyl}-1H-indole-2-carboxylate

[0532] Prepared using the bromide from Preparation 15 the amine frompreparation 36 and the method described for Preparation 8.

[0533]¹H NMR (400 MHz, CDCl₃) δ 8.83 (1H, bs), 7.60-7.50 (6H, m), 7.44(1H, s), 7.41-7.26 (4H, m), 6.98 (1H, d), 5.25 (2H, s), 4.95-4.85 (3H,m), 4.08 (3H, s), 3.03-2.80 (5H, m), 1.95-1.55 (4H, m), 1.10 (3H, t),1.01 (9H, s), 0.18 (3H, s), 0.00 (3H, s).

[0534] LRMS (ESI): m/z [M+H]⁺617.

[0535] Preparation 38:5-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]butyl}-1H-indole-2-carboxylicacid

[0536] Preparation 37 (790 mg, 1.28 mmol) and LiOH (1 M in water, 2.56ml) in THF (40 ml) and water (6 ml) were stirred at RT overnight. Thesolvent was removed in vacuo to yield a yellow foam (870 mg).

[0537] LRMS (APCI): m/z [M+H]⁺603.

[0538] Preparation 39:5-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy{-ethyl{amino)butyl]-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide

[0539] A mixture of Preparation 38 (154 mg, 256 μmol),(1R)-1-phenylethylamine (38 mg, 310 μmol), WSCDI (59 mg, 210 μmol), HOBt(38 mg, 280 μmol) and DIPEA (129 mg, 1.0 mmol) in DMF at RT overnight.The solvent was removed in vacuo and the material taken up in EtOAc,washed with water, brine. The product was purified by chromatography(2-4% MeOH in CH₂Cl₂+0.3% NH₃) to yield a colourless foam (153 mg).

[0540]¹H NMR (400 MHz, CD₃OD): δ 7.27-7.41 (12H, m), 7.20 (1H, m), 7.14(1H, s), 6.92-7.00 (2H, d), 6.65 (1H, d), 5.24 (1H, q), 5.01 (2H, s),4.60-4.70 (3H, m), 2.56-2.89 (5H, m), 1.62-1.52 (4H, m), 1.43 (1H, m),0.97 (3H, t), 0.74 (9H, s), −0.08 (3H, s), −0.26 (3H, s).

[0541] LRMS (ESI): m/z [M]⁺706.

[0542] Preparation 40: Cyclobutylmethylamine

[0543] Borane (1 M in THF, 68 ml, 67.8 mmol) was added dropwise to acooled (0° C.) solution of cyclobutylnitrile (5.0 g, 61.6 mmol) in THF(7 ml) under nitrogen. The mixture was allowed to warm to RT and heatedto reflux for 17 h. The mixture was then cooled to 0° C. and quenched bythe addition of MeOH (81 ml). The mixture was allowed to warm to RT andthe solvent removed. The material was re-dissolved in MeOH (50 ml) andacidified with conc. HCl (50 ml) before being heated to reflux for 2 h.The solvents were removed and the residue triturated with Et₂O and thewhite powder filtered off (4.51 g).

[0544]¹H NMR (400 MHz, CD₃OD): δ 2.95 (2H, d), 2.76 (1H, m), 2.15 (2H,m), 2.05-1.75 (4H, m),

[0545] Analysis: Found C 47.17; H 9.84; N 11.05; C₅H₁₁N₁.HCl 0.3 2H₂Orequires C 47.28; H 10.00; N 11.03.

[0546] Preparation 41:5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(3-methyl-pyridin-2-ylmethyl)-1H-indole-2-carboxamide

[0547] A solution of preparation 6 (200 mg, 400 μmol) in DMF (3 ml) wastreated with O-benzotriazol-1-yl-N,N, N′, N′-tetrauroniumhexafluororphosphate (94 mg, 400 μmol), DIPEA (0.14 ml, 800 μmol) andstirred at RT for 30 min. preparation 42 (49 mg, 400 mmol) in DMF (1 ml)and the solution stirred at 50° C. for 18 h. The solvent was removed invacuo and the crude material dissolved in ethyl acetate (30 ml) andwashed with water (20 ml) and dried (Na₂SO₄). The material was purifiedby chromatography (0-6% MeOH in CH₂Cl₂+0.3% NH₃) to yield a green oilwhich was suspended in diethyl ether and evaporated to yield a whitegreen solid (54 mg).

[0548]¹H NMR (400 MHz, CD₃OD): δ 9.18 (1H, s), 8.42 (1H, d), 8.10 (1H,m), 7.50 (1H, d), 7.15 (2H, m), 6.80-7.00 (3H, m), 6.80 (1H, s), 6.60(1H, d), 4.70-4.90 (5H, m), 2.50-3.10 (5H, m), 2.30 (3H, s), 1.20 (3H,d), 0.80 (9H, s), −0.10 (3H, s), −0.30 (3H, s)

[0549] HRMS: C₃₄H₄₇N₄O₄Si requires: 603.3368 found 603.3365 [M+H]⁺.

[0550] Preparation 42: (3-Methyl-pyridin-2-yl)methylamine

[0551] 3-Methylpyridine-2-carbonitrile (2.0 g, 16.95 mmol) in THF (50ml) at 0° C. was added to a solution of lithium aluminium hydride (16.95ml, 1 M in THF) and the mixture allowed to warm to RT overnight. Thereaction was cooled to 0° C. and quenched with ethyl acetate (2.5 ml).Sodium hydroxide (2.5 ml, 1 M) was added and the mixture stirred at RTfor 1 h, then filtered through Celite®. The filtrate was extracted withethyl acetate (2×20 ml) and the combined organics washed with brine (50ml) and dried (MgSO₄). The crude material was purified by chromatography(0-5% MeOH in CH₂Cl₂+1% NH₃) to yield a yellow oil (282 mg).

[0552]¹H NMR (400 MHz, CDCl₃): δ 8.39 (1H, d), 7.45 (1H, d), 7.12 (1H,dd), 3.50-4.50 (2H, bs), 4.07 (2H, s), 2.29 (3H, s).

[0553] LRMS (ESt): m/z [MH]⁺123, 145 [M+Na]⁺.

[0554] In Vitro Activity of the Indole Derivatives of Formula (1)

[0555] The ability of the indole derivatives of the formula (1) to actas potent β2 agonists therefore mediating smooth muscle relaxation maybe determined by the measure of the effect of beta-2 adrenergic receptorstimulation on electrical field stimulated-contraction of guinea pigtrachea strips.

[0556] Guinea-Pig Trachea

[0557] Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO₂asphyxiation and exsanguination from the femoral artery and the tracheais isolated. Four preparations are obtained from each animal, startingthe dissection immediately below the larynx and taking 2.5 cm length oftrachea. The piece of trachea is opened by cutting the cartilageopposite the trachealis muscle, then transverse sections, 3-4 cartilagerings wide, are cut. The resulting strip preparations are suspended in 5ml organ baths using cotton threads tied through the upper and lowercartilage bands. The strips are equilibrated, un-tensioned, for 20minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μMIndomethacin (Sigma 17378), 10 μM Guanethidine (Sigma G8520) and 10 μMAtenolol (Sigma A7655), heated at 37° C. and gassed with 95% O₂/5% CO₂,before applying an initial tension of 1 g. The preparations are allowedto equilibrate for a further 30-45 minutes, during which time they arere-tensioned (to 1 g) twice at 15-minute intervals. Changes in tensionare recorded and monitored via standard isometric transducers coupled toa data-collection system (custom-designed at Pfizer). Following thetensioning equilibration, the tissues are subjected to electrical fieldstimulation (EFS) using the following parameters: 10 s trains every 2minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts)continuously throughout the length of the experiment. EFS ofpost-ganglionic cholinergic nerves in the trachea results in monophasiccontractions of the smooth muscle and twitch height is recorded. Theorgan baths are constantly perfused with the above-described KrebsRinger buffer by means of a peristaltic pump system (pump flow rate 7.5ml/minute) throughout the experiment, with the exception of when abeta-2 agonist according to the present invention is added, the pump isthen stopped for the time of the cumulative dosing to the bath andstarted again after maximal response is reached for the wash-out period.

[0558] Experimental Protocol for Assessment of Potency and Efficacy

[0559] Following equilibration to EFS, the peristaltic pump is stoppedand the preparations ‘primed’ with a single dose of 300 nM isoprenaline(Sigma 15627) to establish a maximal response in terms of inhibition ofthe contractile EFS response. The isoprenaline is then washed out over aperiod of 40 minutes. Following the priming and wash-out recovery, astandard curve to isoprenaline is carried out on all tissues(Isoprenaline Curve 1) by means of cumulative, bolus addition to thebath using half log increments in concentration. The concentration rangeused is 1^(e-9) to 1^(e)/3^(e-6) M. At the end of the isoprenaline curvethe preparations are washed again for 40 minutes before commencing asecond curve, either to isoprenaline (as internal control) or a beta-2agonist according to the present invention. Beta-2 agonist responses areexpressed as percentage inhibition of the EFS response. Data for beta-2agonist are normalised by expressing inhibition as a percentage of themaximal inhibition induced by isoprenaline in Curve 1. The EC₅₀ valuefor beta-2 agonist according to the present invention refers to theconcentration of compound required to produce half maximal effect. Datafor beta-2 agonists according to the present invention are thenexpressed as relative potency to isoprenaline defined by the ratio (EC₅₀beta-2 agonist)/(EC₅₀ Isoprenaline).

[0560] Confirmation of Beta-2 Mediated Functional Activity

[0561] Beta-2 agonist activity of test compounds is confirmed using theprotocol above, however, prior to constructing the curve to beta-2agonist according to the present invention, the preparations arepre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (aselective β₂ antagonist) which results in the case of a beta-2 mediatedeffect in a rightward-shift of the test compound dose response curve.

[0562] According to another alternative, the agonist potency for the β2receptor of the indole derivatives of the formula (1) may also bedetermined by the measure of the concentration of compound according tothe present invention required to produce half maximal effect (EC₅₀) forthe β2 receptor.

[0563] Compound Preparation

[0564] 10 mM/100% DMSO (dimethylsulfoxide) stock of compound is dilutedto required top dose in 4% DMSO. This top dose is used to construct a10-point semi-log dilution curve, all in 4% DMSO. Isoprenaline (Sigma,I-5627) was used as a standard in every experiment and for control wellson each plate. Data was expressed as % Isoprenaline response.

[0565] Cell Culture

[0566] CHO (Chinese Hamster Ovary) cells recombinantly expressing thehuman P2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2) were grown inDulbeccos MEM/NUT MIX F12 (Gibco, 21331-020) supplemented with 10%foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mMglutamine (Sigma, G7513), 500 μg/ml geneticin (Sigma, G7034) and 10μg/ml puromycin (Sigma, P8833). Cells were seeded to give about 90%confluency for testing.

[0567] Assay Method

[0568] 25 μl/well each dose of compound was transferred into acAMP-Flashplate® (NEN, SMP004B), with 1% DMSO as basal controls and 100nM Isoprenaline as max controls. This was diluted 1:2 by the addition of25 μl/well PBS. Cells were trypsinised (0.25% Sigma, T4049), washed withPBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN,SMP004B) to give 1×10⁶ cells/ml CHOhB2. Compounds were incubated with 50μl/well cells for 1 hour. Cells were then lysed by the addition of 100μl/well detection buffer (NEN, SMP004B) containing 0.18 μCi/ml ¹²⁵I-cAMP(NEN, NEX-130) and plates were incubated at room temperature for afurther 2 hours. The amount of ¹²⁵I-cAMP bound to the Flashplate® wasquantified using a Topcount NXT (Packard), normal counting efficiencyfor 1 minute. Dose-response data was expressed as % Isoprenalineactivity and fitted using a four parameter sigmoid fit.

[0569] It has thus been found that the indole derivatives of formula (1)according to the present invention that are illustrated in examples 1 to18 above show a P2 cAMP EC₅₀ between 0.03 nM and 0.75 nM.

1. A compound of the formula (1):

wherein: a) Q is a saturated 1 to 4 carbon atom chain substituted with a(C₁-C₄)alkyl; R₁ is hydrogen or (C₁-C₄)alkyl; R₂ is hydrogen,(C₁-C₄)alkyl or benzyl optionally substituted with 1, 2 or 3 hydroxy,hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl or NR₉R₁₀; R₃ is hydrogenor (C₁-C₆)alkyl optionally substituted by a hydroxy; A is C₃-C₆cycloalkyl, optionally substituted with hydroxy or (C₁-C₄)alkyl; 5- to10-membered aromatic heterocyclyl containing from 1 to 3 heteroatoms,identical or different, selected from O, S and N, said heterocyclylbeing optionally substituted with (C₁-C₄)alkyl or NR₉R₁₀; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; and R₉ and R₁₀ are identical or different and arehydrogen or (C₁-C₄)alkyl; or b) Q is a single bond or a saturated 1 to 4carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is benzyl optionally substituted with 1, 2or 3 hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo,O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl or NR₉R₁₀; R₃ ishydrogen or (C₁-C₆)alkyl optionally substituted by a hydroxy; A is C₃-C₆cycloalkyl, optionally substituted with hydroxy or (C₁-C₄)alkyl; 5- to10-membered aromatic heterocyclyl containing from 1 to 3 heteroatoms,identical or different, selected from O, S and N, said heterocyclylbeing optionally substituted with (C₁-C₄)alkyl or NR₉R₁₀; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; and R₉ and R₁₀ are identical or different and arehydrogen or (C₁-C₄)alkyl; or c) Q is a single bond or a saturated 1 to 4carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is hydrogen, (C₁-C₄)alkyl or benzyloptionally substituted with 1, 2 or 3 hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl or NR₉R₁₀; R₃ is hydrogen or (C₁-C₆)alkyl optionallysubstituted by a hydroxy; A is C₃-C₆ cycloalkyl, optionally substitutedwith hydroxy or C₁-C₄)alkyl; 5- to 10-membered aromatic heterocyclylcontaining from 1 to 3 heteroatoms, identical or different, selectedfrom O, S and N, said heterocyclyl being optionally substituted with(C₁-C₄)alkyl or NR₉R₁₀; or

 wherein one of R₄, R₅, R₆, R₇ and R₈ is O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀ or NR₉R₁₀ and the remaining R₄, R₅, R₆, R₇ or R₈ are eachindependently hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀,benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,thio(C₁-C₆)alkyl, halo or trifluoromethyl; R₉ and R₁₀ are the same ordifferent and are H or (C₁-C₄)alkyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1 wherein: Q is a saturated 1 to 4carbon atom chain substituted with a (C₁-C₄)alkyl; R₁ is hydrogen or(C₁-C₄)alkyl; R₂ is hydrogen, (C₁-C₄)alkyl or benzyl optionallysubstituted with 1, 2 or 3 hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl or NR₉R₁₀; R₃ is hydrogen or (C₁-C₆)alkyl optionallysubstituted by a hydroxy; A is C₃-C₆ cycloalkyl, optionally substitutedwith hydroxy or (C₁-C₄)alkyl; 5- to 10-membered aromatic heterocyclylcontaining from 1 to 3 heteroatoms, identical or different, selectedfrom O, S and N, said heterocyclyl being optionally substituted with(C₁-C₄)alkyl or NR₉R₁₀; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; and R₉ and R₁₀ are the same or different and are H or(C₁-C₄)alkyl; or a pharmaceutically acceptable salt thereof.
 3. Acompound of claim 1 wherein: Q is a single bond or a saturated 1 to 4carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is benzyl optionally substituted with 1, 2or 3 hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo,O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, trifluoromethyl or NR₉R₁₀; R₃ ishydrogen or (C₁-C₆)alkyl optionally substituted by a hydroxy; A is C₃-C₆cycloalkyl, optionally substituted with hydroxy or (C₁-C₄)alkyl; 5- to10-membered aromatic heterocyclyl containing from 1 to 3 heteroatoms,identical or different, selected from O, Sand N, said heterocyclyl beingoptionally substituted with (C₁-C₄)alkyl or NR₉R₁₀; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; and R₉ and R₁₀ are the same or different and are H or(C₁-C₄)alkyl; or a pharmaceutically acceptable salt thereof.
 4. Acompound of claim 1 wherein: Q is a single bond or a saturated 1 to 4carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is hydrogen, (C₁-C₄)alkyl or benzyloptionally substituted with 1, 2 or 3 hydroxy, hydroxy(C₁-C₆)alkyl,(C₁-C₄)alkyl, (C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl or NR₉R₁₀; R₃ is hydrogen or (C₁-C₆)alkyl optionallysubstituted by a hydroxy; A is C₃-C₆ cycloalkyl, optionally substitutedwith hydroxy or (C₁-C₄)alkyl; 5- to 10-membered aromatic heterocyclylcontaining from 1 to 3 heteroatoms, identical or different, selectedfrom O, S and N, said heterocyclyl being optionally substituted with(C₁-C₄)alkyl or NR₉R₁₀; or

 wherein one of R₄, R₅, R₆, R₇ and R₈ is O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀ or NR₉R₁₀ and the remaining R₄, R₅, R₆, R₇ or R₈ are eachindependently hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀,benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,thio(C₁-C₆)alkyl, halo or trifluoromethyl; and R₉ and R₁₀ are the sameor different and are H or (C₁-C₄)alkyl; or a pharmaceutically acceptablesalt thereof.
 5. A compound of claim 1, 2, 3 or 4 wherein R₁ is methylor ethyl.
 6. A compound of claim 5 wherein R₁ is methyl.
 7. A compoundof claim 1, 2 or 4 wherein R₂ is H, methyl, ethyl or benzyl.
 8. Acompound of claim 1, 2, 3 or 4 wherein R₃ is H or methyl.
 9. A compoundof claim 1, 3 or 4 wherein Q is —CH₂—, —CH₂—CH₂— or —CH(CH₃)—.
 10. Acompound of claim 1 or 2 wherein Q is —CH₂—.
 11. A compound of claim 1,2 or 3 wherein A is C₃-C₆ cycloalkyl; 5 or 6-membered aromaticheterocyclyl containing 1 or 2 heteroatoms selected from O, S and N; or

wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo or trifluoromethyl.
 12. Acompound of claim 1 or 2 wherein: Q is a saturated 1 to 4 carbon atomchain substituted with a (C₁-C₄)alkyl; R₁ is (C₁-C₄)alkyl; R₂ ishydrogen, (C₁-C₄)alkyl or benzyl; R₃ is hydrogen or (C₁-C₆)alkyl; and Ais C₃-C₆ cycloalkyl; 5- or 6-membered aromatic heterocyclyl containingfrom 1 to 3 heteroatoms, identical or different, selected from O, S andN; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 13. Acompound of claim 1 or 3 wherein: Q is a single bond or a saturated 1 to4 carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is benzyl; R₃ is hydrogen or (C₁-C₆)alkyl;and A is C₃-C₆ cycloalkyl; 5- or 6-membered aromatic heterocyclylcontaining from 1 to 3 heteroatoms, identical or different, selectedfrom O, S and N; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀, benzyloxy, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, halo ortrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 14. Acompound of claim 1 or 4 wherein: Q is a single bond or a saturated 1 to4 carbon atom chain optionally substituted with a (C₁-C₄)alkyl; R₁ ishydrogen or (C₁-C₄)alkyl; R₂ is hydrogen, (C₁-C₄)alkyl or benzyl; R₃ ishydrogen or (C₁-C₆)alkyl; and A is C₃-C₆ cycloalkyl; 5- or 6-memberedaromatic heterocyclyl containing from 1 to 3 heteroatoms, identical ordifferent, selected from O, S and N; or

wherein one of R₄, R₅, R₆, R₇ and R₈ is O—CF₃, NR₉SO₂(C₁-C₄)alkyl,SO₂NR₉R₁₀ or NR₉R₁₀ and the remaining R₄, R₅, R₆, R₇ or R₈ are eachindependently hydrogen, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀, NR₉R₁₀,benzyloxy, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,thio(C₁-C₆)alkyl, halo or trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.
 15. A compound of claim 1 or 2 wherein: Q is—CH(CH₃)—; R₁ is methyl or ethyl; R₂ is hydrogen, methyl, ethyl orbenzyl; R₃ is hydrogen or methyl; and A is C₃-C₆ cycloalkyl; 5- or6-membered aromatic heterocyclyl containing 1 or 2 heteroatoms,identical or different, selected from S and N; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀, benzyloxy, hydroxy, methyl, methoxy, ethoxy, thiomethyl, haloor trifluoromethyl.
 16. A compound of claim 15 wherein A is cyclopropyl,cyclopentyl or cyclohexyl.
 17. A compound of claim 15 wherein A ispyridyl or thiazolyl.
 18. A compound of claim 1 or 3 wherein: Q is—CH₂—, —CH₂—CH₂— or —CH(CH₃)—; R₁ is methyl or ethyl; R₂ is benzyl; R₃is hydrogen or methyl; and A is C₃-C₆ cycloalkyl; 5- or 6-memberedaromatic heterocyclyl containing 1 or 2 heteroatoms, identical ordifferent, selected from S and N; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀, benzyloxy, hydroxy, methyl, methoxy, ethoxy, thiomethyl, haloor trifluoromethyl.
 19. A compound of claim 18 wherein A is cyclopropyl,cyclopentyl or cyclohexyl.
 20. A compound of claim 18 wherein A ispyridyl or thiazolyl.
 21. A compound of claim 1 or 4 wherein: Q is—CH₂—, —CH₂—CH₂— or —CH(CH₃)—; R₁ is methyl or ethyl; R₂ is hydrogen,methyl, ethyl or benzyl; R₃ is hydrogen or methyl; and A is C₃-C₆cycloalkyl; 5- or 6-membered aromatic heterocyclyl containing 1 or 2heteroatoms, identical or different, selected from S and N; or

 wherein one of R₄, R₅, R₆, R₇ and R₈ is O—CF₃ or SO₂NR₉R₁₀ and theremaining R₄, R₅, R₆, R₇ or R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀, benzyloxy, hydroxy, methyl, methoxy, ethoxy, thiomethyl, haloor trifluoromethyl.
 22. A compound of claim 21 wherein A is cyclopropyl,cyclopentyl or cyclohexyl.
 23. A compound of claim 21 wherein A ispyridyl or thiazolyl.
 24. A compound of claim 1 or 2 wherein: Q is—CH(CH₃)—; R₁ is methyl or ethyl; R₂ is hydrogen, methyl, ethyl orbenzyl; R₃ is hydrogen; and A is C₃-C₆ cycloalkyl; 5- or 6-memberedaromatic heterocyclyl containing 1 or 2 heteroatoms, identical ordifferent, selected from S and N; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently selected from thegroup consisting of hydrogen, O—CF₃, SO₂NR₉R₁₀ or methoxy.
 25. Acompound of claim 24 wherein A is cyclopropyl, cyclopentyl orcyclohexyl.
 26. A compound of claim 24 wherein A is pyridyl orthiazolyl.
 27. A compound of claim 1 or 3 wherein: Q is —CH₂— or—CH(CH₃)—; R₁ is methyl or ethyl; R₂ is benzyl; R₃ is hydrogen; and A isC₃-C₆ cycloalkyl; 5- or 6-membered aromatic heterocyclyl containing 1 or2 heteroatoms, identical or different, selected from S and N; or

 wherein R₄, R₅, R₆, R₇ and R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀ or methoxy.
 28. A compound of claim 27 wherein A iscyclopropyl, cyclopentyl or cyclohexyl.
 29. A compound of claim 27wherein A is pyridyl or thiazolyl.
 30. A compound of claim 1 or 4wherein: Q is —CH₂— or —CH(CH₃)—; R₁ is methyl or ethyl; R₂ is hydrogen,methyl, ethyl or benzyl; R₃ is hydrogen; and A is C₃-C₆ cycloalkyl; 5-or 6-membered aromatic heterocyclyl containing 1 or 2 heteroatoms,identical or different, selected from S or N; or

wherein one of R₄, R₅, R₆, R₇ and R₈ is O—CF₃ or SO₂NR₉R₁₀ and theremaining R₄, R₅, R₆, R₇ or R₈ are each independently hydrogen, O—CF₃,SO₂NR₉R₁₀ or methoxy.
 31. A compound of claim 30 wherein A iscyclopropyl, cyclopentyl or cyclohexyl.
 32. A compound of claim 30wherein A is pyridyl or thiazolyl. 33.5-[(2R)-2-({(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-trifluoromethoxybenzyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1S)-1-phenylethyl]-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(3-trifluoromethoxyphenylethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(pyridin-2-ylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopropylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl} 10amino)propyl}-N-(thiazol-2-ylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclobutylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(cyclopentylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl phenyl)ethyl}amino)propyl}-N-(cyclohexylmethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-methylsulfamoylbenzyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(4-sulfamoylbenzyl)-1H-indole-2-carboxamide;1-benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2-methoxybenzyl)-1H-indole-2-carboxamide;1-benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide;1-ethyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-2-phenylethyl)-1H-indole-2-carboxamide;5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-[(1R)-1-phenylethyl)-1-methyl-1H-indole-2-carboxamide;1-benzyl-5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)propyl}-N-(2,6-dimethoxybenzyl)-1H-indole-2-carboxamide; or5-[(2R)-2-({(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl}amino)butyl}-N-[(1R)-1-phenylethyl]-1H-indole-2-carboxamide; or apharmaceutically acceptable salt thereof.
 34. A process for preparing acompound of claim 1 comprising coupling an acid of formula (2):

with an amine of formula (3):

wherein R₁, R₂, R₃, Q and A are as defined in claim
 1. 35. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyinnocuous excipient or additive.
 36. A method of treating a disease,disorder or condition mediated by the β2 receptor in a mammal, saidmethod comprising administering a compound of claim 1, 2, 3 or 4 or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of claim 1, 2, 3 or 4 or apharmaceutically acceptable salt thereof and a pharmaceuticallyinnocuous excipient or additive.
 37. A method of claim 36 wherein saiddisease, disorder or condition is asthma, chronic bronchoconstriction,acute bronchoconstriction, chronic bronchitis, small airwaysobstruction, emphysema, obstructive or inflammatory airways diseases,pneumoconiosis, bronchitis, bronchiectasis, central nervous systemdisorders, premature labor, congestive heart failure, depression,inflammatory skin diseases, allergic skin diseases, psoriasis,proliferative skin diseases, glaucoma, gastric ulceration or pepticulceration.
 38. A method of claim 37 wherein said asthma is atopicasthma, non-atopic asthma, allergic asthma, atopic bronchialIgE-mediated asthma, bronchial asthma, essential asthma, true asthma,intrinsic asthma caused by pathophysiologic disturbances, extrinsicasthma caused by environmental factors, essential asthma of unknown orinapparent cause, non-atopic asthma, bronchitic asthma, emphysematousasthma, exercise-induced asthma, allergen induced asthma, cold airinduced asthma, occupational asthma, infective asthma, non-allergicasthma, incipient asthma, wheezy infant syndrome or bronchiolytis. 39.The method of claim 38 wherein said infective asthma is caused bybacterial, fungal, protozoal or viral infection.
 40. The method of claim37 wherein said obstructive or inflammatory airways disease is chroniceosinophilic pneumonia, chronic obstructive pulmonary disease (COPD),COPD associated with chronic bronchitis, COPD associated with pulmonaryemphysema, COPD associated with dyspnea, COPD characterized byirreversible, progressive airways obstruction, adult respiratorydistress syndrome (ARDS), exacerbation of airways hyper-reactivityconsequent to other drug therapy or airways disease associated withpulmonary hypertension.
 41. The method of claim 37 wherein saidpneumoconiosis is aluminosis, bauxite workers' disease, anthracosis,miners' asthma, asbestosis, steam-fitters' asthma, chalicosis, flintdisease, ptilosis caused by inhaling the dust from ostrich feathers,siderosis caused by the inhalation of iron particles, silicosis,grinders' disease, byssinosis, cotton-dust asthma or talcpneumoconiosis.
 42. The method of claim 37 wherein said bronchitis isacute bronchitis, acute laryngotracheal bronchitis, arachidicbronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis,infectious asthmatic bronchitis, productive bronchitis, staphylococcusbronchitis, streptococcal bronchitis or vesicular bronchitis.
 43. Themethod of claim 37 wherein said bronchiectasis is cylindricbronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis,capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis orfollicular bronchiectasis.
 44. The method of claim 37 wherein saidcentral nervous system disorder is depression, Alzheimers disease,Parkinson's disease, learning impairment, memory impairment, tardivedyskinesia, drug dependence, arteriosclerotic dementia, dementiaassociated with Huntington's chorea, Wilson's disease, paralysis agitansor thalamic atrophies.
 45. The method of claim 36 wherein said mammal isa human.
 46. The method of claim 37 wherein said mammal is a human. 47.A compound of formula (2):

wherein R₁ is hydrogen or (C₁-C₄)alkyl; R₂ is benzyl optionallysubstituted with 1, 2 or 3 hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl or NR₉R₁₀; and R₉ and R₁₀ are identical or different andare hydrogen or (C₁-C₄)alkyl.
 48. A compound of formula (4):

wherein R₁ is hydrogen or (C₁-C₄)alkyl; R₂ is benzyl optionallysubstituted with 1, 2 or 3 hydroxy, hydroxy(C₁-C₆)alkyl, (C₁-C₄)alkyl,(C₁-C₆)alkoxy, halo, O—CF₃, NR₉SO₂(C₁-C₄)alkyl, SO₂NR₉R₁₀,trifluoromethyl or NR₉R₁₀; and R₉ and R₁₀ are identical or different andare hydrogen or (C₁-C₄)alkyl.
 49. A compound of claim 47 or 48 whereinR₂ is benzyl.